Department of Biology, Chemistry, Pharmacy

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Peer-reviewed journal articles

2020

[156]

M. Grabowski, M. S. Murgueitio, M. Bermudez, G. Wolber, and G. Weindl. The novel small-molecule antagonist MMG-11 preferentially inhibits TLR2/1 signaling, Biochem Pharmacol, 171:113687, 2020.
Links: [doi:10.1016/j.bcp.2019.113687] [show BibTeX]  x  @article{RN279, author = {Grabowski, Maria and Murgueitio, Manuela S. and Bermudez, Marcel and Wolber, Gerhard and Weindl, Günther}, title = {The novel small-molecule antagonist MMG-11 preferentially inhibits TLR2/1 signaling}, journal = {Biochemical Pharmacology}, volume = {171}, pages = {113687}, ISSN = {0006-2952}, DOI = {https://doi.org/10.1016/j.bcp.2019.113687}, url = {http://www.sciencedirect.com/science/article/pii/S0006295219303867 https://pdf.sciencedirectassets.com/271311/1-s2.0-S0006295219X00118/1-s2.0-S0006295219303867/main.pdf?X-Amz-Security-Token= IQoJb3JpZ2luX2VjENT%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQC1GLXe7oTjeZWHmYev4G3nf5%2FIcgthwBf5dbFg19s9wQIgQVClu3bJsYSWvOCj%2BlmuhxRWuZp087TTTg5rIcRC1gEq2AII7f%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FARACGgwwNTkwMDM1NDY4NjUiDEQ1ucuJyk7Q3xjKfiqsAg1Hlb5Wxzk4NqI8%2Bx%2Fn5aNKanXBkILPhVzjGDnSCOAWFjkcFhrLS3HOroNsTzr6EIqWHkHhY6DXDByrPfeFaqiUyiCmQqOlcZXthUlYbuqtF679ZMHa7e3xh7k92R%2FskTZ4w%2BC%2FUyf3AhY5yxaa%2F6gnpxF2fzW5YuM%2FDOEj60YDSgGqTokG28enoVMf7Kw51snc39RJBaHiudzholZHsdrRpprwBJkywbobi68KKlOqo1pRcaUrxit6YdZlh6mJOH%2FF26lm2NiYenOEMkbUJ7jwTnoqKbzZcyZT5B9cfPvejaRjbk8neyRKwdLDwn1QMRukVcKnLHkHMWqDEqbAKUCWI2dtcGGqdTPRWXrIlc82v0VoU0dh%2FsHiYtkd66nkDCF9%2BM7VKv16LDtyeDDFkqXuBTrQAkkIFedB7tZhSbd10EHuaDGjpQTCtAHQnmAmmR3NDt3T42wnCLUhW%2BpXDA3SMaWNwvr6cm5NNVOdXdtVycYba0a%2Fof8iTtaRzDxWq6aL%2Bg5c2r6%2Flfm9vaQwTFZfYzyfFNcrG9QKSAXDxZgq5GGmM2zYMZBQSJrG4SH661%2F5quartVaMlMcBoP%2FsGsCWnlkUcLP7ggssrbFQUE6RxT0ecnp%2Fs5SuNmx36FegmADW42ngD1P4lf5kUokmTyxMH0R0LlsnyUtDXbRlJqc4hWVBb1RKoBj9eUZyvukC1mOLtgX1zBHeJIj7GFoV1CqRPuTPR%2BSI5hVAsTJfLAAZwTmmOGIHDagPdb7uj7t%2BEq2D3QITPEJgRksv2MUCtR8TfiPkLkGHMnmsywQ1XmFhrhpVe4XO%2BAoXcn1i3qJ8pciPucACFdLRAKWoOL8Q2kiiepDExw%3D%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20191111T130241Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYR4KDMIKJ%2F20191111%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=3eb629cc0ac45e35a4484d837588d002c802da94ab9def7dc45679608ac0a97f&hash=dd504e154491b9c8a639da148b3389b0ab2949305894cf85f55c085f28752274&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0006295219303867&tid=spdf-143941c4-0f50-4946-b075-312001235766&sid=514179e61d3aa24c080bf8d3c53c3ad35d27gxrqb&type=client}, year = {2020}, abtract = {Toll-like receptor 2 (TLR2) forms heterodimers with either TLR1 or TLR6 to induce protective early inflammatory responses to pathogen- and damage-associated molecular patterns. However, excessive activation is associated with inflammatory and metabolic diseases. Several TLR2 antagonists have been described but pharmacological characterization is still at an early stage. Previously, we identified the potent and selective TLR2 antagonist MMG-11 by computational modelling and experimental validation. Here, we characterized the TLR2 antagonists MMG-11 and CU-CPT22 as well as the TIR-domain binding TLR2 antagonist C29 in TLR-overexpressing promoter cells as well as human and mouse macrophages. In line with our recent studies, MMG-11 abrogated pro-inflammatory cytokine secretion and NF-κB activation induced by different bacterial TLR2 agonists. MMG-11 preferentially inhibited TLR2/1 signaling in promoter cells stably expressing TLR2 heterodimers and mouse macrophages. Furthermore, the TLR2 antagonist blocked ligand-induced interaction of TLR2 with MyD88 and reduced MAP kinase and NF-κB activation. MMG-11 and CU-CPT22 but not C29 displaced Pam3CSK4 in an indirect binding assay confirming the competitive mode of action of MMG-11 and CU-CPT22. Isobologram analysis revealed additive and synergistic effects when the non-competitive antagonist C29 was combined with the competitive antagonist MMG-11 or CU-CPT22, respectively. In conclusion, we provide evidence that MMG-11 acts as a competitive antagonist with a predominance for the TLR2/1 heterodimer in human and mouse cells. Our results also indicate that MMG-11 is a model compound for studying TLR2 signaling.}, type = {Journal Article}, keywords = {Inflammation Innate immunity Toll-like receptors TLR2 TLR2/1 heterodimer Competitive antagonist} }

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2019

[155]

L. Agnetta, M. Bermudez, F. Riefolo, C. Matera, E. Claro, R. Messerer, T. Littmann, G. Wolber, U. Holzgrabe, and M. Decker. Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties, J Med Chem, 62(6):3009-3020, 2019.
Links: [doi:10.1021/acs.jmedchem.8b01822] [show BibTeX]  x  @article{RN264, author = {Agnetta, Luca and Bermudez, Marcel and Riefolo, Fabio and Matera, Carlo and Claro, Enrique and Messerer, Regina and Littmann, Timo and Wolber, Gerhard and Holzgrabe, Ulrike and Decker, Michael}, title = {Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties}, journal = {Journal of Medicinal Chemistry}, volume = {62}, number = {6}, pages = {3009-3020}, ISSN = {0022-2623}, DOI = {10.1021/acs.jmedchem.8b01822}, url = {https://doi.org/10.1021/acs.jmedchem.8b01822 https://pubs.acs.org/doi/pdfplus/10.1021/acs.jmedchem.8b01822}, year = {2019}, type = {Journal Article}, keywords = {gpcr} }

[154]

H. Aygun Cevher, D. Schaller, M. A. Gandini, O. Kaplan, E. Gambeta, F. X. Zhang, M. Celebier, M. N. Tahir, G. W. Zamponi, G. Wolber, and M. G. Gunduz. Discovery of Michael acceptor containing 1,4-dihydropyridines as first covalent inhibitors of L-/T-type calcium channels, Bioorg Chem, 91:103187, 2019.
Links: [doi:10.1016/j.bioorg.2019.103187] [show BibTeX]  x  @article{RN276, author = {Aygun Cevher, H. and Schaller, D. and Gandini, M. A. and Kaplan, O. and Gambeta, E. and Zhang, F. X. and Celebier, M. and Tahir, M. N. and Zamponi, G. W. and Wolber, G. and Gunduz, M. G.}, title = {Discovery of Michael acceptor containing 1,4-dihydropyridines as first covalent inhibitors of L-/T-type calcium channels}, journal = {Bioorg Chem}, volume = {91}, pages = {103187}, ISSN = {1090-2120 (Electronic) 0045-2068 (Linking)}, DOI = {10.1016/j.bioorg.2019.103187}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31419643 https://www.sciencedirect.com/science/article/abs/pii/S0045206819309290?via%3Dihub}, year = {2019}, abtract = {1,4-Dihydropyridines (DHPs) are an important class of blockers targeting different calcium channel subtypes and have great therapeutic value against cardiovascular and neurophysiologic conditions. Here, we present the design of DHP-based hexahydroquinoline derivatives as either selective or covalent inhibitors of calcium channels. These compounds were synthesized via a modified Hantzsch reaction under microwave irradiation and characterized by IR, (1)H NMR, (13)C NMR and mass spectra. Additionally, the proposed structure of HM12 was resolved by single crystal X-ray analysis. The abilities of the target compounds to block both L- and T-type calcium channels were evaluated by utilizing the whole-cell patch clamp technique. Our results identified covalent inhibitors of calcium channels for the first time, which could be achieved by introducing a Michael acceptor group into the ester side chain of the compounds. The proposed covalent binding between the compounds and the cysteine amino acid (Cys1492) within the DHP binding pocket of L-type calcium channel was supported by docking and pharmacophore analysis as well as a glutathione reactivity assay.}, type = {Journal Article}, keywords = {Calcium channel blocker Covalent binding Dihydropyridine Hexahydroquinoline Molecular modeling Whole-cell patch clamp} }

[153]

M. Bermudez, T. N. Nguyen, C. Omieczynski, and G. Wolber. Strategies for the discovery of biased GPCR ligands, Drug Discov Today, 24(4):1031-1037, 2019.
Links: [doi:10.1016/j.drudis.2019.02.010] [show BibTeX]  x  @article{RN267, author = {Bermudez, Marcel and Nguyen, Trung Ngoc and Omieczynski, Christian and Wolber, Gerhard}, title = {Strategies for the discovery of biased GPCR ligands}, journal = {Drug Discovery Today}, volume = {24}, number = {4}, pages = {1031-1037}, ISSN = {1359-6446}, DOI = {10.1016/j.drudis.2019.02.010}, url = {http://www.sciencedirect.com/science/article/pii/S1359644618302186 https://pdf.sciencedirectassets.com/271275/1-s2.0-S1359644619X00057/1-s2.0-S1359644618302186/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJGMEQCIBSuXR284U5c9bmAJSN5zVw47n5M5VTNwrBmGQ8hLXVcAiAWIgoCDAYq%2BrLMnoeOj0gcwMsJ%2BK2%2F2vx37jlwfG9V%2FiraAwhBEAIaDDA1OTAwMzU0Njg2NSIMjEBFMn9jIE9t1XN2KrcDLe7GRG%2FXcw3WEgKV9YXbSGYcHYB2z7r%2B9eRerOT0zpE0wRSFgQ%2FOH9BXlp37MIlzoDaMcVajFKZS8gcJXSICZZRdMHztkVCBW4DNZa%2BJxOwJ1E6Q6vzyyBGsc%2FRoV6Xba79A94ndoN8bYy6WNuplWyrl3mWsK2vv7sI6kqAQYvwZAuSo66P%2FLefOdgACsLXUvDUtMMpSN8TmoE6MAFh%2Fj9u1tN2PHd7Si9U0lR%2BPybWjyQIZhRLaPFiPA459dq%2F0DJYDW6PUXjnBlCqj2pjkDd8G%2FcrPGVCvjIs1dEukqNYRPh9wSQFFAb5Fi0wZV3zG%2F46Hc%2FeUQIprBOrsYtxFvQ1UWxSkaVfuuRD2NfJJC%2FoyWTyuxNmD0bdhukh9A21%2B1W83wJfu%2FecDVcxhN9MqXTDLroqrvl%2BRxWFnb%2BWbs%2B%2FV9bgL2cBI6AFt4X60UAEM%2FPSuYh%2FCMbaK1dtKiQLD4N%2F7kxQrpF%2BWzb6z4YOF5hW%2F4Jm%2BgH%2B0v9v9lego%2FcMGf98VdcRdShnMV0057mzmxPdKDL4AivAyKRRfnHrHbLoO1SdPlc41DKXR%2BjK0GtocjZ5j4aUAxDDnpo7rBTq1AThXMgqWLXhCysjiDb69KUDsmtirRuTrXpezLGPDfxkFp5ofIqWUR9J0yQNBLS%2BqlghqmfiGup4DJm90ED%2Bjr269Tuc2Ri4J0zfr7%2BcI1xixL%2Fy0rAQI30TJNbf1CsDGxfVixVDBG1Fkwa3KlpjjfAGAuGKaiPkPOMJuLo8YTbs28PVbbZSstkpcNX0npq661wJ6SM3c0BNDLzt2HCCzsKCoWT8MzDtnFnmY8Er2Z7ayg87lxx0%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090852Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYZNRZYJFV%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=7f58eff199562319314a001e9580c09f4398c03f423e7fcb0c77abbe9f6e7b3f&hash=2eec85bc780a8441b8c56fa4d0c26581dfbc0117ea28d1b8a83af57b9cc39829&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S1359644618302186&tid=spdf-e17f4a4a-0e0c-4d81-94e3-c8ec97d2a8a8&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2019}, abtract = {G-protein-coupled receptors (GPCRs) represent important drug targets with complex pharmacological characteristics. Biased signaling represents one important dimension, describing ligand-dependent shifts of naturally imprinted signaling profiles. Because biased GPCR modulators provide potential therapeutic benefits including higher efficiencies and reduced adverse effects, the identification of such ligands as drug candidates is highly desirable. This review aims to provide an overview of the challenges and strategies in the discovery of biased ligands. We show different approaches for biased ligand discovery in the example of G-protein-biased opioid analgesics and discuss possibilities to design biased ligands by targeting extracellular receptor regions.}, type = {Journal Article}, keywords = {gpcr} }

[152]

P. Durairaj, L. Fan, D. Machalz, G. Wolber, and M. Bureik. Functional characterization and mechanistic modeling of the human cytochrome P450 enzyme CYP4A22, Febs Lett, 593(16):2214-2225, 2019.
Links: [doi:10.1002/1873-3468.13489] [show BibTeX]  x  @article{RN275, author = {Durairaj, Pradeepraj and Fan, Linbing and Machalz, David and Wolber, Gerhard and Bureik, Matthias}, title = {Functional characterization and mechanistic modeling of the human cytochrome P450 enzyme CYP4A22}, journal = {FEBS Letters}, volume = {593}, number = {16}, pages = {2214-2225}, ISSN = {0014-5793}, DOI = {10.1002/1873-3468.13489}, url = {https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1873-3468.13489 https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/1873-3468.13489}, year = {2019}, abtract = {The human cytochrome P450 (CYP) enzyme CYP4A22 is an orphan CYP with unknown function. Here, through functional expression in fission yeast, we show that CYP4A22 catalyzes fatty acid hydroxylation as well as aliphatic or aromatic hydroxylations of luciferin-based probe substrates. Mechanistic molecular modeling of CYP4A22 suggests that its ω-hydroxylation activity is hampered by a more spacious active site compared to CYP4B1. Substrate recognition via side-chains R96 and R233 is indicated by dynamic three-dimensional pharmacophores (dynophores) derived from molecular dynamics simulations. CYP4A22 activity is inhibited by three unspecific CYP inhibitors. A comparison of CYP4A22*1 (the reference standard sequence) with CYP4A22-WT (the most common allele) revealed that for the four substrates tested the WT-enzyme always had lower activity.}, type = {Journal Article}, }

[151]

A. Nass, D. Schaller, and G. Wolber. Assessment of Flexible Shape Complementarity: New Opportunities to Explain and Induce Selectivity in Ligands of Protein Tyrosine Phosphatase 1B, Mol Inform, 38(5):1800141, 2019.
Links: [doi:10.1002/minf.201800141] [show BibTeX]  x  @article{RN268, author = {Nass, A. and Schaller, D. and Wolber, G.}, title = {Assessment of Flexible Shape Complementarity: New Opportunities to Explain and Induce Selectivity in Ligands of Protein Tyrosine Phosphatase 1B}, journal = {Mol Inform}, volume = {38}, number = {5}, pages = {1800141}, ISSN = {1868-1751 (Electronic) 1868-1743 (Linking)}, DOI = {10.1002/minf.201800141}, url = {https://www.ncbi.nlm.nih.gov/pubmed/30725529 https://onlinelibrary.wiley.com/doi/pdf/10.1002/minf.201800141}, year = {2019}, abtract = {For drug design projects it is essential to rationally induce and explain selectivity. In this context shape complementarity as well as protein and ligand flexibility represent important factors. Currently available tools for the analysis of protein-ligand interactions focus mainly on electrostatic complementarity and/or static structures. Here we address the shortcomings of available methods by presenting two new tools: The first one can be used to assess steric complementarity in flexible protein-ligand complexes in order to explain selectivity of known ligands. It further allows to determine ligand atoms with especially good or bad shape-fit which can be of use in lead optimization projects. The second tool was designed to detect differences in protein flexibility in similar proteins along with their exploitation for virtual screening. Both tools yield interesting results when applied to data of protein tyrosine phosphatase 1B (PTP1B): The case of PTP1B has proven especially difficult in terms of selectivity, due to a closely related phosphatase connected to severe undesired effects. With our tool for steric complementarity assessment we were able to explain previously undisclosed causes of moderate selectivity of selected PTP1B ligands. The second tool allowed us to find differences of flexibility in the two highly similar proteins and give directions for exploitation in virtual screening.}, type = {Journal Article}, keywords = {Computational chemistry Molecular dynamics Molecular modeling Selectivity Shape complementarity} }

[150]

M. J. Ojeda-Montes, A. Casanova-Marti, A. Gimeno, S. Tomas-Hernandez, A. Cereto-Massague, G. Wolber, R. Beltran-Debon, C. Valls, M. Mulero, M. Pinent, G. Pujadas, and S. Garcia-Vallve. Mining large databases to find new leads with low similarity to known actives: application to find new DPP-IV inhibitors, Future Med Chem, 11(12):1387-1401, 2019.
Links: [doi:10.4155/fmc-2018-0597] [show BibTeX]  x  @article{RN272, author = {Ojeda-Montes, M. J. and Casanova-Marti, A. and Gimeno, A. and Tomas-Hernandez, S. and Cereto-Massague, A. and Wolber, G. and Beltran-Debon, R. and Valls, C. and Mulero, M. and Pinent, M. and Pujadas, G. and Garcia-Vallve, S.}, title = {Mining large databases to find new leads with low similarity to known actives: application to find new DPP-IV inhibitors}, journal = {Future Med Chem}, volume = {11}, number = {12}, pages = {1387-1401}, ISSN = {1756-8927 (Electronic) 1756-8919 (Linking)}, DOI = {10.4155/fmc-2018-0597}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31298576}, year = {2019}, abtract = {Aim: Fragment-based drug design or bioisosteric replacement is used to find new actives with low (or no) similarity to existing ones but requires the synthesis of nonexisting compounds to prove their predicted bioactivity. Protein-ligand docking or pharmacophore screening are alternatives but they can become computationally expensive when applied to very large databases such as ZINC. Therefore, fast strategies are necessary to find new leads in such databases. Materials & methods: We designed a computational strategy to find lead molecules with very low (or no) similarity to existing actives and applied it to DPP-IV. Results: The bioactivity assays confirm that this strategy finds new leads for DPP-IV inhibitors. Conclusion: This computational strategy reduces the time of finding new lead molecules.}, type = {Journal Article}, keywords = {Cd26 dipeptidyl peptidase 4 diversifying molecular scaffolds expanding chemical space molecular fingerprints virtual molecular libraries virtual screening} }

[149]

R. Ottanà, P. Paoli, G. Lori, I. Adornato, S. Previti, A. Naß, G. Wolber, and R. Maccari. Design and evaluation of non-carboxylate 5-arylidene-2-thioxo-4-imidazolidinones as novel non-competitive inhibitors of protein tyrosine phosphatase 1B, Bioorg Chem, 92:103211, 2019.
Links: [doi:10.1016/j.bioorg.2019.103211] [show BibTeX]  x  @article{RN278, author = {Ottanà, Rosaria and Paoli, Paolo and Lori, Giulia and Adornato, Ilenia and Previti, Santo and Naß, Alexandra and Wolber, Gerhard and Maccari, Rosanna}, title = {Design and evaluation of non-carboxylate 5-arylidene-2-thioxo-4-imidazolidinones as novel non-competitive inhibitors of protein tyrosine phosphatase 1B}, journal = {Bioorganic Chemistry}, volume = {92}, pages = {103211}, ISSN = {00452068}, DOI = {10.1016/j.bioorg.2019.103211}, url = {http://www.sciencedirect.com/science/article/pii/S0045206819307990 https://www.sciencedirect.com/science/article/abs/pii/S0045206819307990?via%3Dihub}, year = {2019}, abtract = {Protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of insulin and leptin signalling and is crucially involved in the development of type 2 diabetes mellitus, obesity, cancer and neurodegenerative diseases. Pursuing our efforts to identify PTP1B inhibitors endowed with drug-like properties, we designed and evaluated 3-aryl-5-arylidene-2-thioxo-4-imidazolidinones (7) as a novel class of non-carboxylate PTP1B inhibitors. In agreement with our design, kinetic studies demonstrated that selected compounds 7 act as reversible, non-competitive inhibitors of the target enzyme at low micromolar concentrations. Accordingly, molecular docking experiments suggested that these inhibitors can fit an allosteric site of PTP1B that we previously individuated. Moreover, cellular assays demonstrated that compound 7e acts as a potent insulin-sensitizing agent in human liver HepG2 cells. Taken together, our results showed that these non-competitive PTP1B inhibitors can be considered promising lead compounds aimed to enhance druggability of the target enzyme and identify novel antidiabetic drugs.}, type = {Journal Article}, keywords = {3-aryl-5-arylidene-2-thioxo-4-imidazolidinones Protein tyrosine phosphatase 1B Non-competitive inhibitors Insulin-sensitizing agents Cellular assays} }

[148]

D. Schaller, S. Hagenow, H. Stark, and G. Wolber. Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands, Plos One, 14(6):e0218820, 2019.
Links: [doi:10.1371/journal.pone.0218820] [show BibTeX]  x  @article{RN274, author = {Schaller, D. and Hagenow, S. and Stark, H. and Wolber, G.}, title = {Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands}, journal = {PLoS One}, volume = {14}, number = {6}, pages = {e0218820}, ISSN = {1932-6203 (Electronic) 1932-6203 (Linking)}, DOI = {10.1371/journal.pone.0218820}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31237914 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592549/pdf/pone.0218820.pdf}, year = {2019}, abtract = {In this study, we report a ligand-guided homology modeling approach allowing the analysis of relevant binding site residue conformations and the identification of two novel histamine H3 receptor ligands with binding affinity in the nanomolar range. The newly developed method is based on exploiting an essential charge interaction characteristic for aminergic G-protein coupled receptors for ranking 3D receptor models appropriate for the discovery of novel compounds through virtual screening.}, type = {Journal Article}, }

[147]

D. Schaller, S. Pach, and G. Wolber. PyRod: Tracing Water Molecules in Molecular Dynamics Simulations, J Chem Inf Model, 59(6):2818-2829, 2019.
Links: [doi:10.1021/acs.jcim.9b00281] [show BibTeX]  x  @article{RN270, author = {Schaller, D. and Pach, S. and Wolber, G.}, title = {PyRod: Tracing Water Molecules in Molecular Dynamics Simulations}, journal = {J Chem Inf Model}, volume = {59}, number = {6}, pages = {2818-2829}, ISSN = {1549-960X (Electronic) 1549-9596 (Linking)}, DOI = {10.1021/acs.jcim.9b00281}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31117512}, year = {2019}, abtract = {Ligands entering a protein binding pocket essentially compete with water molecules for binding to the protein. Hence, the location and thermodynamic properties of water molecules in protein structures have gained increased attention in the drug design community. Including corresponding data into 3D pharmacophore modeling is essential for efficient high throughput virtual screening. Here, we present PyRod, a free and open-source Python software that allows for visualization of pharmacophoric binding pocket characteristics, identification of hot spots for ligand binding, and subsequent generation of pharmacophore features for virtual screening. The implemented routines analyze the protein environment of water molecules in molecular dynamics (MD) simulations and can differentiate between hydrogen bonded waters as well as waters in a protein environment of hydrophobic, charged, or aromatic atom groups. The gathered information is further processed to generate dynamic molecular interaction fields (dMIFs) for visualization and pharmacophoric features for virtual screening. The described software was applied to 5 therapeutically relevant drug targets, and generated pharmacophores were evaluated using DUD-E benchmarking sets. The best performing pharmacophore was found for the HIV1 protease with an early enrichment factor of 54.6. PyRod adds a new perspective to structure-based screening campaigns by providing easy-to-interpret dMIFs and purely protein-based pharmacophores that are solely based on tracing water molecules in MD simulations. Since structural information about cocrystallized ligands is not needed, screening campaigns can be followed, for which less or no ligand information is available. PyRod is freely available at https://github.com/schallerdavid/pyrod .}, type = {Journal Article}, keywords = {software} }

[146]

S. Schramm, L. Agnetta, M. Bermudez, H. Gerwe, M. Irmen, J. Holze, T. Littmann, G. Wolber, C. Trankle, and M. Decker. Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism, ChemMedChem, 14(14):1349-1358, 2019.
Links: [doi:10.1002/cmdc.201900283] [show BibTeX]  x  @article{RN269, author = {Schramm, S. and Agnetta, L. and Bermudez, M. and Gerwe, H. and Irmen, M. and Holze, J. and Littmann, T. and Wolber, G. and Trankle, C. and Decker, M.}, title = {Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism}, journal = {ChemMedChem}, volume = {14}, number = {14}, pages = {1349-1358}, ISSN = {1860-7187 (Electronic) 1860-7179 (Linking)}, DOI = {10.1002/cmdc.201900283}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31166078 https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201900283}, year = {2019}, abtract = {Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1'-(2-tolyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1 -selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.}, type = {Journal Article}, keywords = {GPCRs allostery dualsteric ligands muscarinic receptors partial agonists} }

[145]

D. Sribar, M. Grabowski, M. S. Murgueitio, M. Bermudez, G. Weindl, and G. Wolber. Identification and characterization of a novel chemotype for human TLR8 inhibitors, Eur J Med Chem, 179:744-752, 2019.
Links: [doi:10.1016/j.ejmech.2019.06.084] [show BibTeX]  x  @article{RN273, author = {Sribar, D. and Grabowski, M. and Murgueitio, M. S. and Bermudez, M. and Weindl, G. and Wolber, G.}, title = {Identification and characterization of a novel chemotype for human TLR8 inhibitors}, journal = {Eur J Med Chem}, volume = {179}, pages = {744-752}, ISSN = {1768-3254 (Electronic) 0223-5234 (Linking)}, DOI = {10.1016/j.ejmech.2019.06.084}, url = {https://www.ncbi.nlm.nih.gov/pubmed/31284084 https://pdf.sciencedirectassets.com/271932/1-s2.0-S0223523419X00161/1-s2.0-S0223523419306117/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBfvzJJhZ1Mm5mwy0J3B5VMuELdFjoz7sIRqN8wYSzx3AiEA5SeL7MgEjFO0B9r5FrlpUN4T0hArwMRoS5vGU9JFDzkq2gMIQhACGgwwNTkwMDM1NDY4NjUiDBOT17U1MUqycs1%2FKCq3AxGHFD6W1QLBSzH%2FhBU3v8JJteKuM%2BMlhBDgx9HJr06UFb8BZd%2BHmmbs1ur5t%2FlqtRCT5APQ%2Fzl6M%2FIM8%2F6YwmMYXt9Jyw268%2FtZeBsyIAjhb9UY49j0c7v6aVzNad%2FGYTpVso5RHp%2FRIuM5L67h7pTwnakyTSI6BnpaJqI2B9kWP4JEsZprxWxTmvQw9wKd%2BZ%2Fa4mZjyJSBse7DFly8%2FGnCKXIXFbkL7gEHIAamV19AyDb7zMu0NjKSYkVhnMKdyKtcoydss0kNGXNm7HiEVwqeBYZLCKy4Gr96z9kBNqkcZ%2BCvqAOmMj10aPUlpkLbmx197FcTVJ8VImn9RLlCJRDmDXNX5yS0%2B73PI%2BEazQ5%2BwF1N29hqIzLnT1Cc5utmeZ0G5AMefCBRfmgg6E2TbmfR7Ww0V5jCzNNuAslQXXlpfPN3WJ9keKLw21X%2BSCqBPm%2Fu6Xis2DUor4OC8wohPM2ZjGByx3Gqx2LFJIPCZN3cJyL1gxaivo%2BET3s3jVm6OY0z8nVa20tLJ7Fw2PK6UzrCG3VQ%2F1Wx6deq5BIg0CjfaQgBifcwYqv%2F%2F9ZMxV6ugcNNvcoHxYgw6rmO6wU6tAGkBGWe9a6585563qyrPRyFqAu%2FM2418LDCloFTRDRH9weZ%2BgHQW1B1m%2F%2FVbRWsTdBwvnU%2BOX7Dk7jsNsnZIzAffqBskxE32pvB9%2BEG%2Fi%2F0HR72BRBiQS0zSE42%2F3v4dfwbryhRJ%2FbSj6%2BtUzOYJwiXE%2BTFI6%2Bw6by7InD6OwR0E1IdegTjGtbvA15LPpug9CTJY%2FTVHEISFL2jcir2FrGkZbfPHhgSZLoAg3rn1UL%2Buq%2FcLM4%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090946Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYRDRFHOHF%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=18cc67799361c8f19ea28de71be4d9a9a15278b81c31ee61311a2943791c0028&hash=9bfb87ce149be16e09799114fbfc6758fd8ed8477a8cff5d6739b4a473ea2c5b&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0223523419306117&tid=spdf-db02c76d-e987-4aac-973e-7a3b6205ba36&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2019}, abtract = {The endosomal Toll-like receptor 8 (TLR8) recognizes single-stranded RNA and initiates early inflammatory responses. Despite the importance of endosomal TLRs for human host defense against microbial pathogens, extensive activation may contribute to autoimmune and inflammatory diseases. In contrast to the recent progress made in the development of modulators of plasma membrane-bound TLRs, little is known about endosomal TLR modulation and very few TLR8 inhibitors have been reported. In this study, we discovered and validated novel small-molecule TLR8 inhibitors. Fourteen potential TLR8 modulators were experimentally validated in HEK293T cells stably overexpressing human TLR8 and THP-1 macrophages. Five compounds inhibited TLR8-mediated signaling, representing a hit rate of 36%. The three most potent compounds neither cause cellular toxicity nor inhibition of TLR signaling induced by other receptor subtypes. Conclusively, we experimentally confirm novel and selective, pyrimidine-based TLR8 inhibitors with low cytotoxicity that are relevant candidates for lead optimization and further mechanistic studies.}, type = {Journal Article}, keywords = {Inflammation Inhibitors Pyrimidine scaffold Toll-like receptor 8 Virtual screening} }

[144]

A. Stoll, S. Loke, J. F. Joseph, D. Machalz, X. de la Torre, F. Botrè, G. Wolber, M. Bureik, and M. K. Parr. Fine-mapping of the substrate specificity of human steroid 21-hydroxylase (CYP21A2), The Journal of Steroid Biochemistry and Molecular Biology, :105446, 2019.
Links: [doi:https://.org/10.1016/j.jsbmb.2019.105446] [show BibTeX]  x  @article{RN277, author = {Stoll, Anna and Loke, Steffen and Joseph, Jan Felix and Machalz, David and de la Torre, Xavier and Botrè, Francesco and Wolber, Gerhard and Bureik, Matthias and Parr, Maria Kristina}, title = {Fine-mapping of the substrate specificity of human steroid 21-hydroxylase (CYP21A2)}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, pages = {105446}, ISSN = {0960-0760}, DOI = {https://doi.org/10.1016/j.jsbmb.2019.105446}, url = {http://www.sciencedirect.com/science/article/pii/S0960076019304169 https://pdf.sciencedirectassets.com/271264/1-s2.0-S0960076019X00096/1-s2.0-S0960076019304169/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJr%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBmGoQIBcjjZ5EaOK3PJ%2FGurZx%2F3iAg7AxgzJBGlS1pLAiEAqq3PoXrNmhK0J8VvhGKQxD8CDm2MMxpACdgEvvCDCF0q2gMIQhACGgwwNTkwMDM1NDY4NjUiDB%2FjPXYQeqnKPMIAZSq3Axc0m%2BRD9Wt3prnTKye3Cqvo0AREbqzZ946GaterseGXxpe%2BUb3tyOJVBoXAsvayOEvYdT75FjY53skFYyeai6OYOXjZRWTEelsGyFCQf8cT3DEzx4Q%2FSuFEL5blDoqhss6bszDRC5%2FuVVpSzUmF7%2BFyAgGxxPdatNCbBmiutHGyRMn4PicJgX1DP70wJovm2MIIfOQjtVBAoW1FPcQfo4A0fJI5ShSReUYAnaXr04R8cTE%2BTTnwOVhgNPw19doX3%2FZOAC3wHvx2xdw427PkU7STXll%2FivSFUP2UPMpj5wiro1CxQicswmv0RAWfVQV%2BoN9oIuCE4eWm%2FoT86KudK0SbLCkH8hiO85Gkxien8zQf3J%2BA2aXelkRNwjG55dMxfLKxuLd5mhDnokYj7cOpwsS9sVe2WOpNw0L83GU%2FpuvVJI9vZFARLk225K%2FQ4b1pFcwGOKOAZBiAQZJ9D7JWTWR0gA8Y9KTN%2FrSCDcM7e3OCrDWcifFbCTor1FSCUFanT4fycawD7p8nphvKBxLQcZTmUo0CLG0aAL6hXvuI45m7qu0ijPUXIyCJTvyurXi9RPRuVGihaxkw98KO6wU6tAGChddaHRM2ELzStD4I3%2BltvO8qU5OvXkFpFPXsJT4YQCQafydsDiutI4rsZ8MyFKk2VmqAYvFy3yg9tm4P88k25cm8YxrYD9FZBt34b46IAXloCTW%2BjWdZAQpgxFCuBBURFwPqw%2Bz5EL4gHYjp%2BQW%2FHnmtR8SfofKETRV74Znvs9OncFyjtB09l8I8dyXKRPvZSo%2BtyGyKRjRStMbqfOcty%2BjSd%2FWSyeoJFlE6ZwZclpM4vEI%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090950Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYQ4T4FY7Z%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=e68521637f2f925edb79cb073fbe9fefc601f2c19dfc0856a00eef1bb77d9289&hash=48a45c8b2b325cd841876c27b55a565096a60658bea393cbcbd5a4ba39405d2d&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960076019304169&tid=spdf-6023d6ec-532c-4043-9b99-f4f2eb5c3bdf&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2019}, abtract = {Cytochrome P450 enzymes (CYPs) are capable of catalyzing regio- and stereo-specific oxy functionalization reactions which otherwise are major challenges in organic chemistry. In order to make the best possible use of these biocatalysts it is imperative to understand their specificities. Human CYP21A2 (steroid 21-hydroxylase) acts on the side-chain attached to C-17 in ring D of a steroid substrate, but the configuration of ring A also plays a prominent role in substrate cognition. Here, we comprehensively investigated this relationship using sixteen 17,17-dimethyl-18-nor-13-ene steroids with different arrangements of hydroxy-, oxo-, fluoro- and chloro-groups and in the presence or absence of double bonds (Δ1 and/or Δ4) and heteroatoms in ring A. The results show that presence of a 3-oxo group is a strict requirement for a CYP21A2 substrate, while the other configurations tested were all tolerated. This was also confirmed by control experiments using endogenous steroids. While progesterone and 17-hydroxyprogesterone were hydroxylated at C-21, (17-hydroxy-) pregnenolone did not react. Molecular docking experiments indicate that the interaction of the carbonyl group at C-3 to the side-chain Arg234 of the enzyme is indispensable.}, type = {Journal Article}, keywords = {Cytochrome P450 Fission yeast Gas chromatography mass spectrometry (GCMS) Oral turinabol long-term metabolite Molecular modeling Steroid hydroxylation} }

[143]

N. K. Wenke, J. Kreye, E. Andrzejak, A. van Casteren, J. Leubner, M. S. Murgueitio, S. M. Reincke, C. Secker, L. Schmidl, C. Geis, F. Ackermann, M. Nikolaus, C. C. Garner, H. Wardemann, G. Wolber, and H. Pruess. NMDA receptor dysfunction via unmutated human antibodies against the NR1 subunit, Ann Neurol, 85(5):771-776, 2019.
Links: [doi:10.1002/ana.25460] [show BibTeX]  x  @article{RN266, author = {Wenke, Nina Kerstin and Kreye, Jakob and Andrzejak, Ewa and van Casteren, Adriana and Leubner, Jonas and Murgueitio, Manuela S. and Reincke, S. Momsen and Secker, Christopher and Schmidl, Lars and Geis, Christian and Ackermann, Frauke and Nikolaus, Marc and Garner, Craig C. and Wardemann, Hedda and Wolber, Gerhard and Pruess, Harald}, title = {NMDA receptor dysfunction via unmutated human antibodies against the NR1 subunit}, journal = {Annals of neurology}, volume = {85}, number = {5}, pages = {771-776}, ISSN = {0364-5134}, DOI = {10.1002/ana.25460}, url = {http://europepmc.org/abstract/MED/30843274 https://doi.org/10.1002/ana.25460 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593665/pdf/ANA-85-771.pdf}, year = {2019}, abtract = {Anti‐N‐methyl‐D‐aspartate‐receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid‐derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline‐configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose‐ and time‐dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms.}, type = {Journal Article}, }

[142]

O. Zierau, A. Kolodziejczyk, G. Vollmer, D. Machalz, G. Wolber, D. Thieme, and A. M. Keiler. Comparison of the three SARMs RAD-140, GLPG0492 and GSK-2881078 in two different in vitro bioassays, and in an in silico androgen receptor binding assay, The Journal of Steroid Biochemistry and Molecular Biology, 189:81-86, 2019.
Links: [doi:10.1016/j.jsbmb.2019.02.014] [show BibTeX]  x  @article{RN265, author = {Zierau, Oliver and Kolodziejczyk, Annika and Vollmer, Günter and Machalz, David and Wolber, Gerhard and Thieme, Detlef and Keiler, Annekathrin Martina}, title = {Comparison of the three SARMs RAD-140, GLPG0492 and GSK-2881078 in two different in vitro bioassays, and in an in silico androgen receptor binding assay}, journal = {The Journal of Steroid Biochemistry and Molecular Biology}, volume = {189}, pages = {81-86}, ISSN = {0960-0760}, DOI = {10.1016/j.jsbmb.2019.02.014}, url = {http://www.sciencedirect.com/science/article/pii/S0960076018306885 https://pdf.sciencedirectassets.com/271264/1-s2.0-S0960076019X00047/1-s2.0-S0960076018306885/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJr%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBmGoQIBcjjZ5EaOK3PJ%2FGurZx%2F3iAg7AxgzJBGlS1pLAiEAqq3PoXrNmhK0J8VvhGKQxD8CDm2MMxpACdgEvvCDCF0q2gMIQhACGgwwNTkwMDM1NDY4NjUiDB%2FjPXYQeqnKPMIAZSq3Axc0m%2BRD9Wt3prnTKye3Cqvo0AREbqzZ946GaterseGXxpe%2BUb3tyOJVBoXAsvayOEvYdT75FjY53skFYyeai6OYOXjZRWTEelsGyFCQf8cT3DEzx4Q%2FSuFEL5blDoqhss6bszDRC5%2FuVVpSzUmF7%2BFyAgGxxPdatNCbBmiutHGyRMn4PicJgX1DP70wJovm2MIIfOQjtVBAoW1FPcQfo4A0fJI5ShSReUYAnaXr04R8cTE%2BTTnwOVhgNPw19doX3%2FZOAC3wHvx2xdw427PkU7STXll%2FivSFUP2UPMpj5wiro1CxQicswmv0RAWfVQV%2BoN9oIuCE4eWm%2FoT86KudK0SbLCkH8hiO85Gkxien8zQf3J%2BA2aXelkRNwjG55dMxfLKxuLd5mhDnokYj7cOpwsS9sVe2WOpNw0L83GU%2FpuvVJI9vZFARLk225K%2FQ4b1pFcwGOKOAZBiAQZJ9D7JWTWR0gA8Y9KTN%2FrSCDcM7e3OCrDWcifFbCTor1FSCUFanT4fycawD7p8nphvKBxLQcZTmUo0CLG0aAL6hXvuI45m7qu0ijPUXIyCJTvyurXi9RPRuVGihaxkw98KO6wU6tAGChddaHRM2ELzStD4I3%2BltvO8qU5OvXkFpFPXsJT4YQCQafydsDiutI4rsZ8MyFKk2VmqAYvFy3yg9tm4P88k25cm8YxrYD9FZBt34b46IAXloCTW%2BjWdZAQpgxFCuBBURFwPqw%2Bz5EL4gHYjp%2BQW%2FHnmtR8SfofKETRV74Znvs9OncFyjtB09l8I8dyXKRPvZSo%2BtyGyKRjRStMbqfOcty%2BjSd%2FWSyeoJFlE6ZwZclpM4vEI%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090959Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYQ4T4FY7Z%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=eeebe89dc7b803edab1802d7f7937d0988afcf62b96a832e6f62ad813ee4b3c7&hash=80147c3643733f04f0be90d02fa9badc86eacb637119a9c2ccefcd8a0217a49c&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960076018306885&tid=spdf-742e1312-8b0a-4fb1-a7fe-20eb2f8b370f&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2019}, abtract = {Selective androgen receptor modulators comprise compounds that bind as ligands to the androgen receptor and possess tissue-selective activities. Ideally, they show agonistic properties in anabolic target tissues, while inducing antagonistic or only weak agonistic effects in reproductive organs. Due to their myoanabolic effects, selective androgen receptor modulators are included in the list of prohibited substances and methods of the World Anti-Doping Agency. In the current investigation, the androgenic potential of RAD-140, GSK-2881078 and GLPG0492 was comparably investigated in two different in vitro bioassays. In the yeast androgen screen, the androgenic effects were lower than in the reporter gene assay in prostate carcinoma cells (e.g. for GSK-2881078, the EC50 values were 4.44 × 10−6M in the yeast screen and 3.99 × 10-9M in the prostate cells respectively). For future investigations, it is of importance whether the yeast androgen screen, which has been proven to detect androgenic compounds in urine, can detect an abuse of the selective androgen receptor modulators. Molecular modeling of the binding to the androgen receptor ligand binding domain suggests slight differences in the binding modes of RAD-140, GSK-2881078 and GLPG0492. In conclusion, androgenic activity of the three non-steroidal compounds in the two different in vitro test systems confirmed the results of the in silico modeling of the androgen receptor binding.}, type = {Journal Article}, keywords = {Selective androgen receptor modulators Yeast androgen screen PC3(AR)cells Molecular modeling} }

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2018

[141]

M. Grabowski, M. S. Murgueitio, M. Bermudez, J. Rademann, G. Wolber, and G. Weindl. Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening, Biochem Pharmacol, 154:148-160, 2018.
Links: [doi:10.1016/j.bcp.2018.04.018] [show BibTeX]  x  @article{RN260, author = {Grabowski, Maria and Murgueitio, Manuela S. and Bermudez, Marcel and Rademann, Jörg and Wolber, Gerhard and Weindl, Günther}, title = {Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening}, journal = {Biochemical Pharmacology}, volume = {154}, pages = {148-160}, ISSN = {0006-2952}, DOI = {10.1016/j.bcp.2018.04.018}, url = {http://www.sciencedirect.com/science/article/pii/S0006295218301618 https://pdf.sciencedirectassets.com/271311/1-s2.0-S0006295218X00070/1-s2.0-S0006295218301618/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBfvzJJhZ1Mm5mwy0J3B5VMuELdFjoz7sIRqN8wYSzx3AiEA5SeL7MgEjFO0B9r5FrlpUN4T0hArwMRoS5vGU9JFDzkq2gMIQhACGgwwNTkwMDM1NDY4NjUiDBOT17U1MUqycs1%2FKCq3AxGHFD6W1QLBSzH%2FhBU3v8JJteKuM%2BMlhBDgx9HJr06UFb8BZd%2BHmmbs1ur5t%2FlqtRCT5APQ%2Fzl6M%2FIM8%2F6YwmMYXt9Jyw268%2FtZeBsyIAjhb9UY49j0c7v6aVzNad%2FGYTpVso5RHp%2FRIuM5L67h7pTwnakyTSI6BnpaJqI2B9kWP4JEsZprxWxTmvQw9wKd%2BZ%2Fa4mZjyJSBse7DFly8%2FGnCKXIXFbkL7gEHIAamV19AyDb7zMu0NjKSYkVhnMKdyKtcoydss0kNGXNm7HiEVwqeBYZLCKy4Gr96z9kBNqkcZ%2BCvqAOmMj10aPUlpkLbmx197FcTVJ8VImn9RLlCJRDmDXNX5yS0%2B73PI%2BEazQ5%2BwF1N29hqIzLnT1Cc5utmeZ0G5AMefCBRfmgg6E2TbmfR7Ww0V5jCzNNuAslQXXlpfPN3WJ9keKLw21X%2BSCqBPm%2Fu6Xis2DUor4OC8wohPM2ZjGByx3Gqx2LFJIPCZN3cJyL1gxaivo%2BET3s3jVm6OY0z8nVa20tLJ7Fw2PK6UzrCG3VQ%2F1Wx6deq5BIg0CjfaQgBifcwYqv%2F%2F9ZMxV6ugcNNvcoHxYgw6rmO6wU6tAGkBGWe9a6585563qyrPRyFqAu%2FM2418LDCloFTRDRH9weZ%2BgHQW1B1m%2F%2FVbRWsTdBwvnU%2BOX7Dk7jsNsnZIzAffqBskxE32pvB9%2BEG%2Fi%2F0HR72BRBiQS0zSE42%2F3v4dfwbryhRJ%2FbSj6%2BtUzOYJwiXE%2BTFI6%2Bw6by7InD6OwR0E1IdegTjGtbvA15LPpug9CTJY%2FTVHEISFL2jcir2FrGkZbfPHhgSZLoAg3rn1UL%2Buq%2FcLM4%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090857Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYRDRFHOHF%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=52ad4fdabb56638c2c8b04f45e3af465d312eb783e4c682b7408391bf1547167&hash=86710a46965e7b1d9c59f82aee323ae1a049611d27dfe297837ca19738cb00f4&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0006295218301618&tid=spdf-76629106-1834-4408-8ac7-5788bb298bd2&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2018}, abtract = {Toll-like receptor 2 (TLR2) induces early inflammatory responses to pathogen and damage-associated molecular patterns trough heterodimerization with either TLR1 or TLR6. Since overstimulation of TLR2 signaling is linked to several inflammatory and metabolic diseases, TLR2 antagonists may provide therapeutic benefits for the control of inflammatory conditions. We present virtual screening for the identification of novel TLR2 modulators, which combines analyses of known ligand sets with structure-based approaches. The 13 identified compounds were pharmacologically characterized in HEK293-hTLR2 cells, THP-1 macrophages and peripheral blood mononuclear cells for their ability to inhibit TLR2-mediated responses. Four out of 13 selected compounds show concentration-dependent activity, representing a hit rate of 31%. The most active compound is the pyrogallol derivative MMG-11 that inhibits both TLR2/1 and TLR2/6 signaling and shows a higher potency than the previously discovered CU-CPT22. Concentration ratio analysis identified both compounds as competitive antagonists of Pam3CSK4- and Pam2CSK4-induced responses. Schild plot analysis yielded apparent pA2 values of 5.73 and 6.15 (TLR2/1), and 5.80 and 6.65 (TLR2/6) for CU-CPT22 and MMG-11, respectively. MMG-11 neither shows cellular toxicity nor interference with signaling induced by other TLR agonists, IL-1β or TNF. Taken together, we demonstrate that MMG-11 is a potent and selective TLR2 antagonist with low cytotoxicity rendering it a promising pharmacological tool for the investigation of TLR signaling and a suitable lead structure for further chemical optimization.}, type = {Journal Article}, keywords = {Drug discovery Toll-like receptors TLR2 Virtual screening Competitive antagonist tlr} }

[140]

A. M. Keiler, O. Zierau, S. Wolf, P. Diel, W. Schänzer, G. Vollmer, D. Machalz, G. Wolber, and M. K. Parr. Androgen- and estrogen-receptor mediated activities of 4-hydroxytestosterone, 4-hydroxyandrostenedione and their human metabolites in yeast based assays, Toxicol Lett, 292:39-45, 2018.
Links: [doi:10.1016/j.toxlet.2018.04.026] [show BibTeX]  x  @article{RN256, author = {Keiler, Annekathrin Martina and Zierau, Oliver and Wolf, Sylvi and Diel, Patrick and Schänzer, Wilhelm and Vollmer, Günter and Machalz, David and Wolber, Gerhard and Parr, Maria Kristina}, title = {Androgen- and estrogen-receptor mediated activities of 4-hydroxytestosterone, 4-hydroxyandrostenedione and their human metabolites in yeast based assays}, journal = {Toxicology Letters}, volume = {292}, pages = {39-45}, ISSN = {0378-4274}, DOI = {10.1016/j.toxlet.2018.04.026}, url = {http://www.sciencedirect.com/science/article/pii/S0378427418301644 https://www.sciencedirect.com/science/article/pii/S0378427418301644?via%3Dihub}, year = {2018}, abtract = {4-Hydroxyandrost-4-ene-3,17-dione, also named formestane, is an irreversible aromatase inhibitor and therapeutically used as anti-breast cancer medication in post-menopausal women. Currently, no therapeutical indication led to approval of its 17-hydroxylated analog 4-hydroxytestosterone, an anabolic steroid. However, it is currently investigated in a clinical trial for breast cancer. In context with sports doping, aromatase inhibitors are administered to reduce estrogenic side effects of misused anabolic substances or their metabolites. Therefore, both substances are prohibited in sports by the World Anti-Doping Agency (WADA). Analysis of urinary phase I and phase II metabolites showed similar results for both compounds. In the current investigation, 4-hydroxyandrost-4-ene-3,17-dione, 4-hydroxytestosterone and seven of their described urinary metabolites as well as 2α-hydroxyandrostenedione were tested in the yeast androgen screen and the yeast estrogen screen. Androgenic effects were observed for all tested substances, except for one, which showed anti-androgenic properties. With regard to the yeast estrogen screen, estrogenic effects were observed for only two metabolites at rather high concentrations, while six out of the ten substances tested showed anti-estrogenic properties. In terms of the strong androgenic effect observed for 4-hydroxytestosterone (10−8 M), 4-hydroxyandrost-4-ene-3,17-dione (10−8 M) and two more urinary metabolites, the yeast androgen assay may also be used to trace abuse in urine samples.}, type = {Journal Article}, keywords = {Formestane 4-Hydroxytestosterone Doping Molecular modeling} }

[139]

J. Liu, L. Chen, J. F. Joseph, A. Naß, A. Stoll, X. de la Torre, F. Botrè, G. Wolber, M. K. Parr, and M. Bureik. Combined chemical and biotechnological production of 20βOH-NorDHCMT, a long-term metabolite of Oral-Turinabol (DHCMT), J Inorg Biochem, 183:165-171, 2018.
Links: [doi:10.1016/j.jinorgbio.2018.02.020] [show BibTeX]  x  @article{RN257, author = {Liu, Jiaxin and Chen, Lei and Joseph, Jan Felix and Naß, Alexandra and Stoll, Anna and de la Torre, Xavier and Botrè, Francesco and Wolber, Gerhard and Parr, Maria Kristina and Bureik, Matthias}, title = {Combined chemical and biotechnological production of 20βOH-NorDHCMT, a long-term metabolite of Oral-Turinabol (DHCMT)}, journal = {Journal of Inorganic Biochemistry}, volume = {183}, pages = {165-171}, ISSN = {0162-0134}, DOI = {10.1016/j.jinorgbio.2018.02.020}, url = {http://www.sciencedirect.com/science/article/pii/S0162013417308516 https://pdf.sciencedirectassets.com/271941/1-s2.0-S0162013418X0004X/1-s2.0-S0162013417308516/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJGMEQCIBSuXR284U5c9bmAJSN5zVw47n5M5VTNwrBmGQ8hLXVcAiAWIgoCDAYq%2BrLMnoeOj0gcwMsJ%2BK2%2F2vx37jlwfG9V%2FiraAwhBEAIaDDA1OTAwMzU0Njg2NSIMjEBFMn9jIE9t1XN2KrcDLe7GRG%2FXcw3WEgKV9YXbSGYcHYB2z7r%2B9eRerOT0zpE0wRSFgQ%2FOH9BXlp37MIlzoDaMcVajFKZS8gcJXSICZZRdMHztkVCBW4DNZa%2BJxOwJ1E6Q6vzyyBGsc%2FRoV6Xba79A94ndoN8bYy6WNuplWyrl3mWsK2vv7sI6kqAQYvwZAuSo66P%2FLefOdgACsLXUvDUtMMpSN8TmoE6MAFh%2Fj9u1tN2PHd7Si9U0lR%2BPybWjyQIZhRLaPFiPA459dq%2F0DJYDW6PUXjnBlCqj2pjkDd8G%2FcrPGVCvjIs1dEukqNYRPh9wSQFFAb5Fi0wZV3zG%2F46Hc%2FeUQIprBOrsYtxFvQ1UWxSkaVfuuRD2NfJJC%2FoyWTyuxNmD0bdhukh9A21%2B1W83wJfu%2FecDVcxhN9MqXTDLroqrvl%2BRxWFnb%2BWbs%2B%2FV9bgL2cBI6AFt4X60UAEM%2FPSuYh%2FCMbaK1dtKiQLD4N%2F7kxQrpF%2BWzb6z4YOF5hW%2F4Jm%2BgH%2B0v9v9lego%2FcMGf98VdcRdShnMV0057mzmxPdKDL4AivAyKRRfnHrHbLoO1SdPlc41DKXR%2BjK0GtocjZ5j4aUAxDDnpo7rBTq1AThXMgqWLXhCysjiDb69KUDsmtirRuTrXpezLGPDfxkFp5ofIqWUR9J0yQNBLS%2BqlghqmfiGup4DJm90ED%2Bjr269Tuc2Ri4J0zfr7%2BcI1xixL%2Fy0rAQI30TJNbf1CsDGxfVixVDBG1Fkwa3KlpjjfAGAuGKaiPkPOMJuLo8YTbs28PVbbZSstkpcNX0npq661wJ6SM3c0BNDLzt2HCCzsKCoWT8MzDtnFnmY8Er2Z7ayg87lxx0%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090907Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYZNRZYJFV%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=b720f3d2263dac5174d9f180a9eb5e614b3e41a49d79c0654e5cf2db83daf8ac&hash=b75427625e4bad8f5793e591fc5f3d24775b20f57d1f3e4528dd1440c335f22e&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0162013417308516&tid=spdf-730e9d0a-0d56-4e6a-a6a4-f7f6e8e867cf&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2018}, abtract = {Anabolic androgenic steroids (AAS) are misused very frequently in sport competitions as performance enhancing agents. One of the doping compounds that has been detected with increased frequency in the last few years is dehydrochloromethyltestosterone (DHCMT, 4-chloro-17β-hydroxy-17α-methylandrosta-1,4-dien-3-one; brand name Oral Turinabol). The long-term DHCMT metabolite 20βOH-NorDHCMT (4-chloro-17β-hydroxymethyl-17α-methyl-18-norandrosta-1,4,13-trien-3-one) was reported earlier to be detectable in urine samples for more than 22 days after DHCMT administration; however, purified reference material was not available so far. In this study we demonstrate a successful combination of Wagner-Meerwein rearrangement of DHCMT to NorDHCMT (4-chloro-17,17-dimethyl-18-norandrosta-1,4,13-trien-3-one) and subsequent whole-cell biotransformation with a recombinant fission yeast strain expressing the human cytochrome P450 enzyme (CYP or P450) CYP21A2 for the synthesis of mg amounts of this metabolite. It was then used as reference for the analysis of a post administration urine of DHCMT. The availability of this reference compound will provide an incontestable proof for DHCMT abuse.}, type = {Journal Article}, keywords = {Anabolic androgenic steroids Doping Fission yeast Whole-cell biotransformation} }

[138]

R. Maccari, A. Del Corso, P. Paoli, I. Adornato, G. Lori, F. Balestri, M. Cappiello, A. Naß, G. Wolber, and R. Ottana. An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications, Bioorg Med Chem Lett, :, 2018.
Links: [doi:10.1016/j.bmcl.2018.10.024] [show BibTeX]  x  @article{RN261, author = {Maccari, Rosanna and Del Corso, Antonella and Paoli, Paolo and Adornato, Ilenia and Lori, Giulia and Balestri, Francesco and Cappiello, Mario and Naß, Alexandra and Wolber, Gerhard and Ottana, Rosaria}, title = {An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications}, journal = {Bioorganic & Medicinal Chemistry Letters}, ISSN = {0960-894X}, DOI = {10.1016/j.bmcl.2018.10.024}, url = {http://www.sciencedirect.com/science/article/pii/S0960894X18308254 https://pdf.sciencedirectassets.com/271398/1-s2.0-S0960894X18X00225/1-s2.0-S0960894X18308254/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBfvzJJhZ1Mm5mwy0J3B5VMuELdFjoz7sIRqN8wYSzx3AiEA5SeL7MgEjFO0B9r5FrlpUN4T0hArwMRoS5vGU9JFDzkq2gMIQhACGgwwNTkwMDM1NDY4NjUiDBOT17U1MUqycs1%2FKCq3AxGHFD6W1QLBSzH%2FhBU3v8JJteKuM%2BMlhBDgx9HJr06UFb8BZd%2BHmmbs1ur5t%2FlqtRCT5APQ%2Fzl6M%2FIM8%2F6YwmMYXt9Jyw268%2FtZeBsyIAjhb9UY49j0c7v6aVzNad%2FGYTpVso5RHp%2FRIuM5L67h7pTwnakyTSI6BnpaJqI2B9kWP4JEsZprxWxTmvQw9wKd%2BZ%2Fa4mZjyJSBse7DFly8%2FGnCKXIXFbkL7gEHIAamV19AyDb7zMu0NjKSYkVhnMKdyKtcoydss0kNGXNm7HiEVwqeBYZLCKy4Gr96z9kBNqkcZ%2BCvqAOmMj10aPUlpkLbmx197FcTVJ8VImn9RLlCJRDmDXNX5yS0%2B73PI%2BEazQ5%2BwF1N29hqIzLnT1Cc5utmeZ0G5AMefCBRfmgg6E2TbmfR7Ww0V5jCzNNuAslQXXlpfPN3WJ9keKLw21X%2BSCqBPm%2Fu6Xis2DUor4OC8wohPM2ZjGByx3Gqx2LFJIPCZN3cJyL1gxaivo%2BET3s3jVm6OY0z8nVa20tLJ7Fw2PK6UzrCG3VQ%2F1Wx6deq5BIg0CjfaQgBifcwYqv%2F%2F9ZMxV6ugcNNvcoHxYgw6rmO6wU6tAGkBGWe9a6585563qyrPRyFqAu%2FM2418LDCloFTRDRH9weZ%2BgHQW1B1m%2F%2FVbRWsTdBwvnU%2BOX7Dk7jsNsnZIzAffqBskxE32pvB9%2BEG%2Fi%2F0HR72BRBiQS0zSE42%2F3v4dfwbryhRJ%2FbSj6%2BtUzOYJwiXE%2BTFI6%2Bw6by7InD6OwR0E1IdegTjGtbvA15LPpug9CTJY%2FTVHEISFL2jcir2FrGkZbfPHhgSZLoAg3rn1UL%2Buq%2FcLM4%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090911Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYRDRFHOHF%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=feaf53b1f39ea803adab835418ba489cae4c6b949016e91c0fc74405f2220c83&hash=ec623c4bd4a7063e8d68152bb19a69be7b6f0203d7e5e52fe53b81ddea1e14ee&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960894X18308254&tid=spdf-441f1cff-7ad6-4594-91a9-39f8bcc7b983&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2018}, abtract = {Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1–17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.}, type = {Journal Article}, keywords = {Diabetes mellitus Designed multiple ligands 4-Thiazolidinone derivatives Aldose reductase Protein tyrosine phosphatase 1B} }

[137]

R. Maccari, R. Ettari, I. Adornato, A. Naß, G. Wolber, A. Bitto, F. Mannino, F. Aliquo, G. Bruno, F. Nicolo, S. Previti, S. Grasso, M. Zappala, and R. Ottana. Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors, Bioorg Med Chem Lett, 28(3):278-283, 2018.
Links: [doi:10.1016/j.bmcl.2017.12.053] [show BibTeX]  x  @article{RN251, author = {Maccari, Rosanna and Ettari, Roberta and Adornato, Ilenia and Naß, Alexandra and Wolber, Gerhard and Bitto, Alessandra and Mannino, Federica and Aliquo, Federica and Bruno, Giuseppe and Nicolo, Francesco and Previti, Santo and Grasso, Silvana and Zappala, Maria and Ottana, Rosaria}, title = {Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors}, journal = {Bioorganic & Medicinal Chemistry Letters}, volume = {28}, number = {3}, pages = {278-283}, ISSN = {0960-894X}, DOI = {10.1016/j.bmcl.2017.12.053}, url = {http://www.sciencedirect.com/science/article/pii/S0960894X17312271 https://www.sciencedirect.com/science/article/pii/S0960894X17312271?via%3Dihub https://pdf.sciencedirectassets.com/271398/1-s2.0-S0960894X18X0002X/1-s2.0-S0960894X17312271/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQDpMFAxqO8i5cWwO8J2bidQOOPWWOgX2xYgjlCqnmYpKAIgMz6zEqJOOqjcysWG%2F%2BjDZIPEG4hPysl42TQ%2BxrkJgLgq2gMIQRACGgwwNTkwMDM1NDY4NjUiDMbVMeQJp%2BA6xuTeeiq3A5yGUmiSxbecX6zyK9C0u9d8FvveGrkPLG2bgf%2FLpoQrYo2WyvA%2BBWqUubZ%2F%2F2lzFcSTpeDFbT3qjC0N3gXJAnlrhfnB4HtdM5JkFOs7rk4T5uxWa2QB%2Bxrb0uGWp6C%2FKniuq6eBMiJ59EW8Qua9SC1HjapOsfuus9g5HoQTBdya%2B%2B93vPUyT1l6n3DvNF79aTePLdf4GzCoc3La3CqQwXZ%2Bv00XVVkSLXyHqEtn%2BKj4RqGYDx5vybmCYgNtuQnt%2F4u%2FKij1yfRzcl%2BKOheRiB2UBQBFkx%2BGRL%2BqBFLx23kYZU2PrVD4ZjQMMXyglfn7R41W1Ts944jcTs7eKtPEaIuwbGZFi3rfxU%2BBL%2BrhXsqDJMbPTE%2BrqYpk6xiwMVJaY6kJH62kCLazVZrQ49cjhJjxeJti4aqVRxjr4XOP%2FJ9EatP%2BZoD3q47yNzrS1dG3FcQOp6Rtx1LGD9QPU8GrLpoB2%2F%2BrydWuCVqCFWw5iNbyp05sWQsfmSpFEMzsvkKO%2FCw0bATpkHdkF6WOn0A1lXIOsI0cDUPAe1xWJ3L0KZySQ0UZUqXJ8Gw4v%2FTlL5BY%2FUxSnor26xYwn6aO6wU6tAHBqopuW5pcz%2FJI%2BrCyUdYGVL8ZGUcN9osxZNHlsdHl%2FPSb5Ey3HqdiHTks1pszrFK8F0ZxsQNCYajkgKT3SAzhgrTmaNYfXyzLVkl3rMbW5QA0SqgsnR79JfHgUXuHGBnWyrsVF5mu9vmFjpTB4j2VqmtMOIjghMdHO%2FOIcR59ey2VTJQKE1Ulq0WJqECO72nl8nHMFEUoBLcWlCu5cwJlo5NxAcL7qC1hNPBzJlNFYMqU07s%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090916Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY5J43SP76%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=e7c2580b1bb9072e94b21c17a17e77638c77cc9426365c1d5789e72f4ef95b81&hash=61d4515aaf52ead90206956d3b9b1b4f62c4062ab11c5f1b52d8f8dd8b4e4eb5&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960894X17312271&tid=spdf-2602928c-1628-4f42-ac59-ecd3a11225cf&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2018}, abtract = {This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with Ki values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.}, type = {Journal Article}, keywords = {Proteasome Immunoproteasome 5-Arylidene-2-thioxoimidazolidin-4-ones Non-covalent inhibitors Docking studies} }

[136]

D. Schaller, M. G. Gündüz, F. X. Zhang, G. W. Zamponi, and G. Wolber. Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity, Eur J Med Chem, 155:1-12, 2018.
Links: [doi:10.1016/j.ejmech.2018.05.032] [show BibTeX]  x  @article{RN258, author = {Schaller, David and Gündüz, Miyase Gözde and Zhang, Fang Xiong and Zamponi, Gerald W. and Wolber, Gerhard}, title = {Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity}, journal = {European Journal of Medicinal Chemistry}, volume = {155}, pages = {1-12}, ISSN = {0223-5234}, DOI = {10.1016/j.ejmech.2018.05.032}, url = {https://www.sciencedirect.com/science/article/pii/S0223523418304458 https://pdf.sciencedirectassets.com/271932/1-s2.0-S0223523418X00129/1-s2.0-S0223523418304458/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQDpMFAxqO8i5cWwO8J2bidQOOPWWOgX2xYgjlCqnmYpKAIgMz6zEqJOOqjcysWG%2F%2BjDZIPEG4hPysl42TQ%2BxrkJgLgq2gMIQRACGgwwNTkwMDM1NDY4NjUiDMbVMeQJp%2BA6xuTeeiq3A5yGUmiSxbecX6zyK9C0u9d8FvveGrkPLG2bgf%2FLpoQrYo2WyvA%2BBWqUubZ%2F%2F2lzFcSTpeDFbT3qjC0N3gXJAnlrhfnB4HtdM5JkFOs7rk4T5uxWa2QB%2Bxrb0uGWp6C%2FKniuq6eBMiJ59EW8Qua9SC1HjapOsfuus9g5HoQTBdya%2B%2B93vPUyT1l6n3DvNF79aTePLdf4GzCoc3La3CqQwXZ%2Bv00XVVkSLXyHqEtn%2BKj4RqGYDx5vybmCYgNtuQnt%2F4u%2FKij1yfRzcl%2BKOheRiB2UBQBFkx%2BGRL%2BqBFLx23kYZU2PrVD4ZjQMMXyglfn7R41W1Ts944jcTs7eKtPEaIuwbGZFi3rfxU%2BBL%2BrhXsqDJMbPTE%2BrqYpk6xiwMVJaY6kJH62kCLazVZrQ49cjhJjxeJti4aqVRxjr4XOP%2FJ9EatP%2BZoD3q47yNzrS1dG3FcQOp6Rtx1LGD9QPU8GrLpoB2%2F%2BrydWuCVqCFWw5iNbyp05sWQsfmSpFEMzsvkKO%2FCw0bATpkHdkF6WOn0A1lXIOsI0cDUPAe1xWJ3L0KZySQ0UZUqXJ8Gw4v%2FTlL5BY%2FUxSnor26xYwn6aO6wU6tAHBqopuW5pcz%2FJI%2BrCyUdYGVL8ZGUcN9osxZNHlsdHl%2FPSb5Ey3HqdiHTks1pszrFK8F0ZxsQNCYajkgKT3SAzhgrTmaNYfXyzLVkl3rMbW5QA0SqgsnR79JfHgUXuHGBnWyrsVF5mu9vmFjpTB4j2VqmtMOIjghMdHO%2FOIcR59ey2VTJQKE1Ulq0WJqECO72nl8nHMFEUoBLcWlCu5cwJlo5NxAcL7qC1hNPBzJlNFYMqU07s%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090934Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY5J43SP76%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=c849855703227baf4068983f2ec0fd8823703c021692f5938ab30d1eb2fa9bff&hash=2b4e25a1b06c86632253879a8372204f4f5ae2a04e12ae7231cd5b4a48705142&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0223523418304458&tid=spdf-307057ac-8507-41f8-9a2e-60eca516f2bb&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2018}, abtract = {Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes. In this study, we identified a common binding mode for prominent DHPs nifedipine and isradipine using docking and pharmacophore analysis that is also able to explain the structure-activity relationship of a small subseries of DHP derivatives with a condensed ring system. These findings were used to guide the synthesis of twenty-two novel DHPs. An extensive characterization using 1H NMR, 13C NMR, mass spectra and elemental analysis was followed by whole cell patch clamp assays for analyzing activity at Cav1.2 and Cav3.2. Two compounds were identified with significant activity against Cav1.2. Additionally, we identified four compounds active against Cav3.2 of which three were selective over Cav1.2. Novel binding modes were analyzed using docking and pharmacophore analysis as well as molecular dynamics simulations.}, type = {Journal Article}, keywords = {1,4-dihydropyridine Hexahydroquinoline Calcium channel Whole cell patch clamp Binding mechanism Molecular modelling} }

[135]

R. Schulz, A. Atef, D. Becker, F. Gottschalk, C. Tauber, S. Wagner, C. Arkona, A. A. Abdel-Hafez, H. H. Farag, J. Rademann, and G. Wolber. Phenylthiomethyl ketone-based fragments show selective and irreversible inhibition of enteroviral 3C proteases, J Med Chem, 61(3):1218-1230, 2018.
Links: [doi:10.1021/acs.jmedchem.7b01440] [show BibTeX]  x  @article{RN252, author = {Schulz, Robert and Atef, Amira and Becker, Daniel and Gottschalk, Franziska and Tauber, Carolin and Wagner, Stefan and Arkona, Christoph and Abdel-Hafez, Atef A. and Farag, Hassan H. and Rademann, Jörg and Wolber, Gerhard}, title = {Phenylthiomethyl ketone-based fragments show selective and irreversible inhibition of enteroviral 3C proteases}, journal = {Journal of Medicinal Chemistry}, volume = {61}, number = {3}, pages = {1218-1230}, ISSN = {0022-2623}, DOI = {10.1021/acs.jmedchem.7b01440}, url = {http://dx.doi.org/10.1021/acs.jmedchem.7b01440 https://pubs.acs.org/doi/pdfplus/10.1021/acs.jmedchem.7b01440}, year = {2018}, abtract = {Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry. We describe a systematic and rational computational approach for the identification of covalently binding fragments from compound collections inhibiting enteroviral 3C protease, a target with high therapeutic potential. By implementing reactive groups potentially forming covalent bonds as chemical feature in our 3D pharmacophore methodology, covalent binders were discovered by high-throughput virtual screening. We present careful experimental validation of the virtual hits using enzymatic assays and mass spectrometry unraveling a novel, previously unknown irreversible inhibition of the 3C protease by phenylthiomethyl ketone-based fragments. Subsequent synthetic optimization through fragment growing and reactivity analysis against catalytic and non-catalytic cysteines revealed specific irreversible 3C protease inhibition.}, type = {Journal Article}, }

[134]

A. Tkachenko, M. Bermudez, S. Irmer-Stooff, D. Genkinger, F. Henkler-Stephani, G. Wolber, and A. Luch. Nuclear transport of the human aryl hydrocarbon receptor and subsequent gene induction relies on its residue histidine 291, Arch Toxicol, 92(3):1151-1160, 2018.
Links: [doi:10.1007/s00204-017-2129-0] [show BibTeX]  x  @article{RN249, author = {Tkachenko, A. and Bermudez, M. and Irmer-Stooff, S. and Genkinger, D. and Henkler-Stephani, F. and Wolber, G. and Luch, A.}, title = {Nuclear transport of the human aryl hydrocarbon receptor and subsequent gene induction relies on its residue histidine 291}, journal = {Archives of Toxicology}, volume = {92}, number = {3}, pages = {1151-1160}, ISSN = {1432-0738}, DOI = {10.1007/s00204-017-2129-0}, url = {https://doi.org/10.1007/s00204-017-2129-0 https://link.springer.com/content/pdf/10.1007%2Fs00204-017-2129-0.pdf}, year = {2018}, abtract = {The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in the metabolism of physiological substances and xenobiotics, representing an interesting target in both toxicology and pharmacology. In this study, we investigated the ligand-dependent conjunction of nuclear import of the human AHR in living cells and target gene induction. Our findings strengthen the theory that the AHR triggers a precisely defined and rapid reaction upon binding to endogenous ligands, while the xenobiotic β-naphthoflavone only induces rather unspecific and slow effects. To better illuminate the ligand-mediated responses of the human AHR, we applied site-directed mutagenesis and identified histidine 291 as key residue for AHR functionality, essential for both nuclear import and target gene induction. Contrary, replacing histidine at position 291 by alanine did not affect nucleo-cytoplasmic shuttling, showing that permanent endogenous import and ligand-induced import of the AHR into the nucleus are two independent and differently regulated processes. Combining these observations with our structural investigations using a homology model of the AHR-PAS B domain, we suggest a dual role of histidine 291: (1) a major role for shaping the ligand binding site including direct interactions with ligands and, (2) an essential role for the conformational dynamics of a PAS B loop, which most likely influences the association of the AHR with the AHR nuclear translocator through interference with their protein–protein interface.}, type = {Journal Article}, }

[133]

F. Yang, D. Machalz, S. Wang, Z. Li, G. Wolber, and M. Bureik. A common polymorphic variant of UGT1A5 displays increased activity due to optimized cofactor binding, Febs Lett, 592(11):1837-1846, 2018.
Links: [doi:10.1002/1873-3468.13072] [show BibTeX]  x  @article{RN259, author = {Yang, Fan and Machalz, David and Wang, Sisi and Li, Zhengyi and Wolber, Gerhard and Bureik, Matthias}, title = {A common polymorphic variant of UGT1A5 displays increased activity due to optimized cofactor binding}, journal = {FEBS Letters}, volume = {592}, number = {11}, pages = {1837-1846}, DOI = {10.1002/1873-3468.13072}, url = {https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1873-3468.13072 https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/1873-3468.13072}, year = {2018}, abtract = {Uridine diphosphate‐glucuronosyltransferases (UGTs) are the most important phase II enzymes in human drug metabolism. Using permeabilized recombinant fission yeast cells (enzyme bags), we demonstrate that UGT1A5 can catalyze an N‐glucuronidation reaction. We characterized two new polymorphic UGT1A5 variants: a common ninefold mutant (UGT1A5*8) with double‐fold activity and a much rarer sixfold mutant (UGT1A5*9), which has the same activity as the wild‐type. Molecular modeling studies indicate that the minor effects of all mutations, except for Gly259Arg, are due to their distance to the substrate binding site. Extensive molecular dynamics simulations revealed that the Gly259Arg mutation stabilizes helix Q through a newly formed hydrogen bonding network, which places the cofactor in a much more favorable geometry in UGT1A5*8 as compared to the wild‐type.}, type = {Journal Article}, }

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2017

[132]

H. A. Abuelizz, R. Al-Salahi, J. Al-Asri, J. Mortier, M. Marzouk, E. Ezzeldin, A. A. Ali, M. G. Khalil, G. Wolber, H. A. Ghabbour, A. A. Almehizia, and G. A. Abdel Jaleel. Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives, Chem Cent J, 11(1):103, 2017.
Links: [doi:10.1186/s13065-017-0321-1] [show BibTeX]  x  @article{RN207, author = {Abuelizz, Hatem A. and Al-Salahi, Rashad and Al-Asri, Jamil and Mortier, Jérémie and Marzouk, Mohamed and Ezzeldin, Essam and Ali, Azza A. and Khalil, Mona G. and Wolber, Gerhard and Ghabbour, Hazem A. and Almehizia, Abdulrahman A. and Abdel Jaleel, Gehad A.}, title = {Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives}, journal = {Chemistry Central Journal}, volume = {11}, number = {1}, pages = {103}, ISSN = {1752-153X}, DOI = {10.1186/s13065-017-0321-1}, url = {https://doi.org/10.1186/s13065-017-0321-1 https://ccj.springeropen.com/track/pdf/10.1186/s13065-017-0321-1?site= ccj.springeropen.com}, year = {2017}, abtract = {The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scaffold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was conducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure–activity relationship of the synthesized compounds. The structures of the synthesized compounds were confirmed by HREI-MS, and NMR spectra along with X-ray diffraction were collected for products 1 and 5. Thereafter, anti-inflammatory effect of molecules 1–20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibition potency in albino rats with an activity comparable to that of the standard drugs indomethacin. Compounds 8, 9, 15 and 16 showed the highest anti-inflammatory activity. However, thermal sensitivity-hot plat test, a radiological examination and motor coordination assessment were performed to test the activity against rheumatoid arthritis. The obtained results indicate promising anti-arthritic activity for compounds 9 and 15 as significant reduction of the serum level of interleukin-1β [IL-1β], cyclooxygenase-2 [COX-2] and prostaglandin E2 [PGE2] was observed in CFA rats.}, type = {Journal Article}, }

[131]

M. Bermudez, A. Bock, F. Krebs, U. Holzgrabe, K. Mohr, M. J. Lohse, and G. Wolber. Ligand-specific restriction of extracellular conformational dynamics constrains signaling of the M2 muscarinic receptor, ACS Chem Biol, 12(7):1743-1748, 2017.
Links: [doi:10.1021/acschembio.7b00275] [show BibTeX]  x  @article{RN203, author = {Bermudez, Marcel and Bock, Andreas and Krebs, Fabian and Holzgrabe, Ulrike and Mohr, Klaus and Lohse, Martin J. and Wolber, Gerhard}, title = {Ligand-specific restriction of extracellular conformational dynamics constrains signaling of the M2 muscarinic receptor}, journal = {ACS Chemical Biology}, volume = {12}, number = {7}, pages = {1743-1748}, DOI = {10.1021/acschembio.7b00275}, url = {http://pubs.acs.org/doi/pdfplus/10.1021/acschembio.7b00275}, year = {2017}, abtract = {G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and β-arrestins. Some pathways may be therapeutically beneficial, whereas others may be detrimental under certain pathophysiological conditions. For many GPCRs, biased agonists are available, which preferentially signal through one pathway or a subset of pathways, and harnessing biased agonism could be a potential novel therapeutic strategy. However, the incomplete mechanistic understanding of biased agonism hampers rational design of biased ligands. Using the muscarinic M2 receptor as a model system, we have analyzed the relationship between ligand-dependent conformational changes as revealed in all-atom MD simulations and the activation of specific G proteins. We find that the extent of closure of the extracellular, allosteric binding site interferes with the activation of certain G proteins. Our data allow the rational design of Gi-biased agonists at the M2 receptor and delineate a simple principle which may be translated to other GPRCs.}, type = {Journal Article}, keywords = {gpcr} }

[130]

J. Mortier, J. R. C. Prévost, D. Sydow, S. Teuchert, C. Omieczynski, M. Bermudez, R. Frédérick, and G. Wolber. Arginase Structure and Inhibition: Catalytic Site Plasticity Reveals New Modulation Possibilities, Scientific Reports, 7(1):13616, 2017.
Links: [doi:10.1038/s41598-017-13366-4] [show BibTeX]  x  @article{RN248, author = {Mortier, Jérémie and Prévost, Julien R. C. and Sydow, Dominique and Teuchert, Sabine and Omieczynski, Christian and Bermudez, Marcel and Frédérick, Raphaël and Wolber, Gerhard}, title = {Arginase Structure and Inhibition: Catalytic Site Plasticity Reveals New Modulation Possibilities}, journal = {Scientific Reports}, volume = {7}, number = {1}, pages = {13616}, ISSN = {2045-2322}, DOI = {10.1038/s41598-017-13366-4}, url = {https://doi.org/10.1038/s41598-017-13366-4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648838/pdf/41598_2017_Article_13366.pdf}, year = {2017}, abtract = {Metalloenzyme arginase is a therapeutically relevant target associated with tumor growth. To fight cancer immunosuppression, arginase activity can be modulated by small chemical inhibitors binding to its catalytic center. To better understand molecular mechanisms of arginase inhibition, a careful computer-aided mechanistic structural investigation of this enzyme was conducted. Using molecular dynamics (MD) simulations in the microsecond range, key regions of the protein active site were identified and their flexibility was evaluated and compared. A cavity opening phenomenon was observed, involving three loops directly interacting with all known ligands, while metal coordinating regions remained motionless. A novel dynamic 3D pharmacophore analysis method termed dynophores has been developed that allows for the construction of a single 3D-model comprising all ligand-enzyme interactions occurring throughout a complete MD trajectory. This new technique for the in silico study of intermolecular interactions allows for loop flexibility analysis coupled with movements and conformational changes of bound ligands. Presented MD studies highlight the plasticity of the size of the arginase active site, leading to the hypothesis that larger ligands can enter the cavity of arginase. Experimental testing of a targeted fragment library substituted by different aliphatic groups validates this hypothesis, paving the way for the design of arginase inhibitors with novel binding patterns.}, type = {Journal Article}, keywords = {dynophore} }

[129]

M. S. Murgueitio, S. Ebner, P. Hörtnagl, C. Rakers, R. Bruckner, P. Henneke, G. Wolber, and S. Santos-Sierra. Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2), Biochimica et Biophysica Acta (BBA) - General Subjects, 1861(11):2680-2689, 2017.
Links: [doi:10.1016/j.bbagen.2017.07.011] [show BibTeX]  x  @article{RN205, author = {Murgueitio, M. S. and Ebner, S. and Hörtnagl, P. and Rakers, C. and Bruckner, R. and Henneke, P. and Wolber, G. and Santos-Sierra, S.}, title = {Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2)}, journal = {Biochimica et Biophysica Acta (BBA) - General Subjects}, volume = {1861}, number = {11}, pages = {2680-2689}, ISSN = {0304-4165}, DOI = {10.1016/j.bbagen.2017.07.011}, url = {http://www.sciencedirect.com/science/article/pii/S0304416517302222 https://ac.els-cdn.com/S0304416517302222/1-s2.0-S0304416517302222-main.pdf?_tid= 0e5b1604-ba65-11e7-9947-00000aab0f27&acdnat=1509033065_be28cc321c81e00bd2ec48eb34559e40}, year = {2017}, abtract = {Emergent therapies in anticancer vaccination use Toll-like receptors (TLRs) agonists as dendritic cell (DC) vaccine adjuvants. DCs from the patient are isolated, stimulated with TLR agonists and tumor antigens ex vivo and then infused back into the patient. Although some TLR ligands have been tested in clinical trials, novel TLR agonists with improved immunomodulatory properties are essential to optimize treatment success. We report on the discovery of small-molecule TLR2 agonists, with favorable properties as synthetic adjuvants. We performed a shape- and featured-based similarity virtual screening against a commercially available compound library. The selected virtual hits were experimentally tested in TLR2-reporter cells and their activity in phagocytes and DCs was characterized. A binding model of the compounds to TLR2 (docking studies) was proposed. Through a virtual screening approach against a library of three million compounds four virtual hits (AG1, AG2, AG3, AG4) were found to synergistically augment the NF-kB activation induced by the lipopeptide ligand Pam3CSK4 in luciferase reporter assays using HEK293-TLR2 cells. Biacore experiments indicated that AG1–AG4 are ago-allosteric modulators of TLR2 and AG2 bound TLR2 with high affinity (KD 0.8μM). The compounds induced TNF-α production in human peripheral blood mononuclear cells (PBMCs) and they activated DCs as indicated by IL-12 production and upregulation of CD83/CD86. Following a combined in silico/in vitro approach we have discovered TLR2-agonists (AG1–AG4) that activate human and mouse immune cells. We introduce four novel TLR2 ago-allosteric modulators that stimulate myeloid cell activity and constitute promising candidates as synthetic adjuvants.}, type = {Journal Article}, keywords = {Toll-like receptor Cancer vaccination Virtual screening Adjuvants Dendritic cell Inflammation} }

[128]

M. S. Murgueitio, C. Rakers, A. Frank, and G. Wolber. Balancing Inflammation: Computational Design of Small-Molecule Toll-like Receptor Modulators, Trends Pharmacol Sci, 38(2):155-168, 2017.
Links: [doi:10.1016/j.tips.2016.10.007] [show BibTeX]  x  @article{RN201, author = {Murgueitio, Manuela S. and Rakers, Christin and Frank, Anne and Wolber, Gerhard}, title = {Balancing Inflammation: Computational Design of Small-Molecule Toll-like Receptor Modulators}, journal = {Trends in Pharmacological Sciences}, volume = {38}, number = {2}, pages = {155-168}, ISSN = {0165-6147}, DOI = {10.1016/j.tips.2016.10.007}, url = {http://dx.doi.org/10.1016/j.tips.2016.10.007 http://ac.els-cdn.com/S0165614716301377/1-s2.0-S0165614716301377-main.pdf?_tid= 8ea85ae0-b7c0-11e6-8b76-00000aab0f27&acdnat=1480595013_5bb0b3aaeb0d4f16e65dd6468b9b7091}, year = {2017}, abtract = {As essential proteins of the innate immune system, Toll-like receptors (TLRs) are involved in a plethora of physiological pathologies and their modulation is an ongoing quest in the field of drug discovery. Although TLRs recognize an unusually broad range of different molecular patterns, only a few small-molecule TLR modulators have been reported to date. Recent advances in crystallography and in silico techniques provide promising opportunities for TLR investigations and drug design. Here, three application areas for computational approaches are considered: (i) exploration of TLR structure and activation; (ii) understanding TLR modulation; and (iii) TLR drug discovery. By providing an overview on state-of-the-art computational methods, we highlight the value of molecular modeling in mechanistically understanding TLR function and guiding drug design.}, type = {Journal Article}, }

[127]

R. Ottana, P. Paoli, A. Naß, G. Lori, V. Cardile, I. Adornato, A. Rotondo, A. C. Eleonora Graziano, G. Wolber, and R. Maccari. Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents, Eur J Med Chem, 127:840-858, 2017.
Links: [doi:10.1016/j.ejmech.2016.10.063] [show BibTeX]  x  @article{RN199, author = {Ottana, Rosaria and Paoli, Paolo and Naß, Alexandra and Lori, Giulia and Cardile, Venera and Adornato, Ilenia and Rotondo, Archimede and Eleonora Graziano, Adriana Carol and Wolber, Gerhard and Maccari, Rosanna}, title = {Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents}, journal = {European Journal of Medicinal Chemistry}, volume = {127}, pages = {840-858}, ISSN = {0223-5234}, DOI = {10.1016/j.ejmech.2016.10.063}, url = {http://www.sciencedirect.com/science/article/pii/S0223523416309345 http://ac.els-cdn.com/S0223523416309345/1-s2.0-S0223523416309345-main.pdf?_tid= 72e236fe-ed3b-11e6-8bc2-00000aab0f6c&acdnat=1486475206_d6dd5764eee03f4148356c005814f688}, year = {2017}, abtract = {New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated. Docking experiments suggested that certain derivatives 5 and 6 may efficiently fit into an allosteric site positioned between the β-sheet including Leu71 and Lys73 and a lipophilic pocket closed by the loop consisting of Pro210 to Leu 204. In cellular assays, several of these new 4-thiazolidinone derivatives showed insulinomimetic and anti-inflammatory properties. Out of them, compound 5b exhibited the most promising profile, being able to promote the activation of both insulin receptor and downstream Akt protein as well as to increase 2-deoxyglucose cellular uptake. Interestingly, compound 5b was also able to interrupt critical events in inflammatory signalling.}, type = {Journal Article}, keywords = {Protein tyrosine phosphatases Enzyme inhibitors Insulinomimetic effects Anti-inflammatory activity Molecular docking 5-Arylidene-4-thiazolidinone derivatives} }

[126]

F. Sanz, F. Pognan, T. Steger-Hartmann, C. Díaz, M. Cases, M. Pastor, P. Marc, J. Wichard, K. Briggs, D. K. Watson, T. Kleinöder, C. Yang, A. Amberg, M. Beaumont, A. J. Brookes, S. Brunak, M. T. D. Cronin, G. F. Ecker, S. Escher, N. Greene, A. Guzmán, A. Hersey, P. Jacques, L. Lammens, J. Mestres, W. Muster, H. Northeved, M. Pinches, J. Saiz, N. Sajot, A. Valencia, J. van der Lei, N. P. E. Vermeulen, E. Vock, G. Wolber, and I. Zamora. Legacy data sharing to improve drug safety assessment: the eTOX project, Nat Rev Drug Discov, 16:811, 2017.
Links: [doi:10.1038/nrd.2017.177] [show BibTeX]  x  @article{RN250, author = {Sanz, Ferran and Pognan, François and Steger-Hartmann, Thomas and Díaz, Carlos and Cases, Montserrat and Pastor, Manuel and Marc, Philippe and Wichard, Joerg and Briggs, Katharine and Watson, David K. and Kleinöder, Thomas and Yang, Chihae and Amberg, Alexander and Beaumont, Maria and Brookes, Anthony J. and Brunak, Søren and Cronin, Mark T. D. and Ecker, Gerhard F. and Escher, Sylvia and Greene, Nigel and Guzmán, Antonio and Hersey, Anne and Jacques, Pascale and Lammens, Lieve and Mestres, Jordi and Muster, Wolfgang and Northeved, Helle and Pinches, Marc and Saiz, Javier and Sajot, Nicolas and Valencia, Alfonso and van der Lei, Johan and Vermeulen, Nico P. E. and Vock, Esther and Wolber, Gerhard and Zamora, Ismael}, title = {Legacy data sharing to improve drug safety assessment: the eTOX project}, journal = {Nature Reviews Drug Discovery}, volume = {16}, pages = {811}, DOI = {10.1038/nrd.2017.177}, url = {http://dx.doi.org/10.1038/nrd.2017.177 http://www.nature.com/articles/nrd.2017.177.pdf}, year = {2017}, type = {Journal Article}, }

[125]

D. Schaller, S. Hagenow, G. Alpert, A. Naß, R. Schulz, M. Bermudez, H. Stark, and G. Wolber. Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands, ACS Medicinal Chemistry Letters, 8(6):648-653, 2017.
Links: [doi:10.1021/acsmedchemlett.7b00118] [show BibTeX]  x  @article{RN202, author = {Schaller, David and Hagenow, Stefanie and Alpert, Gina and Naß, Alexandra and Schulz, Robert and Bermudez, Marcel and Stark, Holger and Wolber, Gerhard}, title = {Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands}, journal = {ACS Medicinal Chemistry Letters}, volume = {8}, number = {6}, pages = {648-653}, DOI = {10.1021/acsmedchemlett.7b00118}, url = {http://dx.doi.org/10.1021/acsmedchemlett.7b00118 http://pubs.acs.org/doi/pdfplus/10.1021/acsmedchemlett.7b00118}, year = {2017}, abtract = {In this study, we report a ligand-centric data mining approach that guided the identification of suitable target profiles for treating obesity. The newly developed method is based on identifying target pairs for synergistic positive effects and also encompasses the exclusion of compounds showing a detrimental effect on obesity treatment (off-targets). Ligands with known activity against obesity-relevant targets were compared using fingerprint representations. Similar compounds with activities to different targets were evaluated for the mechanism of action since activation or deactivation of drug targets determines the pharmacological effect. In vitro validation of the modeling results revealed that three known modulators of melanin-concentrating hormone receptor 1 (MCHR1) show a previously unknown submicromolar affinity to the histamine H3 receptor (H3R). This synergistic activity may present a novel therapeutic option against obesity.}, type = {Journal Article}, keywords = {gpcr} }

[124]

Q. Yan, D. Machalz, A. Zöllner, E. J. Sorensen, G. Wolber, and M. Bureik. Efficient substrate screening and inhibitor testing of human CYP4Z1 using permeabilized recombinant fission yeast, Biochem Pharmacol, 146:174-187, 2017.
Links: [doi:10.1016/j.bcp.2017.09.011] [show BibTeX]  x  @article{RN206, author = {Yan, Qi and Machalz, David and Zöllner, Andy and Sorensen, Erik J. and Wolber, Gerhard and Bureik, Matthias}, title = {Efficient substrate screening and inhibitor testing of human CYP4Z1 using permeabilized recombinant fission yeast}, journal = {Biochemical Pharmacology}, volume = {146}, pages = {174-187}, ISSN = {0006-2952}, DOI = {10.1016/j.bcp.2017.09.011}, url = {http://www.sciencedirect.com/science/article/pii/S000629521730607X}, year = {2017}, abtract = {We have established a protocol for the preparation of permeabilized fission yeast cells (enzyme bags) that recombinantly express human cytochrome P450 enzymes (CYPs). A direct comparison of CYP3A4 activity gave an eightfold higher space-time yield for enzyme bag-catalyzed biotransformation as compared to whole-cell biotransformation, even though the total number of cells employed was lower by a factor of 150. Biotransformation of the luminogenic substrate Luciferin-H using CYP2C9-containing enzyme bags proceeded efficiently and stably for 24h. CYP4Z1 is of interest because it is strongly overexpressed both in breast cancer cells and in breast cancer metastases; however, current knowledge about its catalytic properties is very limited. Screening of CYP4Z1-containing enzyme bags with 15 luminogenic substrates enabled us to identify two new hydroxylations and eleven ether cleavage reactions that are catalyzed by CYP4Z1. By far the best substrate found in this study was Luciferin benzyl ether (Luciferin-BE). On the basis of the recently published crystal structure of CYP4B1 we created a new homology model of CYP4Z1 and performed molecular docking experiments, which indicate that all active substrates show a highly similar binding geometry compared to the endogenous substrates. The model predicts that Ser113, Ser222, Asn381, and Ser383 are key hydrogen bonding residues. We also identified five new inhibitors of CYP4Z1: miconazole, econazole, aminobenzotriazole, tolazoline, and 1-benzylimidazole respectively, with the last compound being the most potent giving an IC50 value of 180nM in our test system.}, type = {Journal Article}, keywords = {Human cytochrome P450 Biotransformation Fission yeast Hydroxylation Ether cleavage} }

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2016

[123]

J. Al-Asri, G. Gyémánt, E. Fazekas, G. Lehoczki, M. F. Melzig, G. Wolber, and J. Mortier. α-Amylase Modulation: Discovery of Inhibitors Using a Multi-Pharmacophore Approach for Virtual Screening, ChemMedChem, 11(21):2372-2377, 2016.
Links: [doi:10.1002/cmdc.201600427] [show BibTeX]  x  @article{RN200, author = {Al-Asri, Jamil and Gyémánt, Gyöngyi and Fazekas, Erika and Lehoczki, Gábor and Melzig, Matthias F. and Wolber, Gerhard and Mortier, Jérémie}, title = {α-Amylase Modulation: Discovery of Inhibitors Using a Multi-Pharmacophore Approach for Virtual Screening}, journal = {ChemMedChem}, volume = {11}, number = {21}, pages = {2372-2377}, ISSN = {1860-7187}, DOI = {10.1002/cmdc.201600427}, url = {http://dx.doi.org/10.1002/cmdc.201600427 http://onlinelibrary.wiley.com/store/10.1002/cmdc.201600427/asset/cmdc201600427.pdf?v= 1&t=iw6bvytr&s=b1ae9a27fb0f290b45c6a6997a8a3e9dff7b9678}, year = {2016}, abtract = {Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α-amylase initiates the hydrolysis of polysaccharides, the design of α-amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer-aided approach was developed to identify novel α-amylase inhibitors. Three-dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme. In a stepwise virtual screening workflow, seven molecules were selected from a library of 1.4 million. Five out of seven biologically tested compounds showed α-amylase inhibition, and the two most potent compounds inhibited α-amylase with IC50 values of 17 and 27 μm. The scaffold benzylideneacetohydrazide was shared by four of the discovered inhibitors, emerging as a novel drug-like non-carbohydrate fragment and constituting a promising lead scaffold for α-amylase inhibition.}, type = {Journal Article}, keywords = {α-amylase computer-aided drug design diabetes high-throughput virtual screening lead discovery obesity} }

[122]

D. Becker, Z. Kaczmarska, C. Arkona, R. Schulz, C. Tauber, G. Wolber, R. Hilgenfeld, M. Coll, and J. Rademann. Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments, Nat Commun, 7:12761, 2016.
Links: [doi:10.1038/ncomms12761] [show BibTeX]  x  @article{RN198, author = {Becker, Daniel and Kaczmarska, Zuzanna and Arkona, Christoph and Schulz, Robert and Tauber, Carolin and Wolber, Gerhard and Hilgenfeld, Rolf and Coll, Miquel and Rademann, Jörg}, title = {Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments}, journal = {Nature Communications}, volume = {7}, pages = {12761}, DOI = {10.1038/ncomms12761}, url = {http://dx.doi.org/10.1038/ncomms12761 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052702/pdf/ncomms12761.pdf}, year = {2016}, type = {Journal Article}, }

[121]

M. Bermudez, J. Mortier, C. Rakers, D. Sydow, and G. Wolber. More than a look into a crystal ball: protein structure elucidation guided by molecular dynamics simulations, Drug Discov Today, 21(11):1799-1805, 2016.
Links: [doi:10.1016/j.drudis.2016.07.001] [show BibTeX]  x  @article{RN193, author = {Bermudez, Marcel and Mortier, Jeremie and Rakers, Christin and Sydow, Dominique and Wolber, Gerhard}, title = {More than a look into a crystal ball: protein structure elucidation guided by molecular dynamics simulations}, journal = {Drug Discovery Today}, volume = {21}, number = {11}, pages = {1799-1805}, ISSN = {1359-6446}, DOI = {10.1016/j.drudis.2016.07.001}, url = {http://www.sciencedirect.com/science/article/pii/S1359644616302513 https://pdf.sciencedirectassets.com/271275/1-s2.0-S1359644616X00128/1-s2.0-S1359644616302513/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIQDpMFAxqO8i5cWwO8J2bidQOOPWWOgX2xYgjlCqnmYpKAIgMz6zEqJOOqjcysWG%2F%2BjDZIPEG4hPysl42TQ%2BxrkJgLgq2gMIQRACGgwwNTkwMDM1NDY4NjUiDMbVMeQJp%2BA6xuTeeiq3A5yGUmiSxbecX6zyK9C0u9d8FvveGrkPLG2bgf%2FLpoQrYo2WyvA%2BBWqUubZ%2F%2F2lzFcSTpeDFbT3qjC0N3gXJAnlrhfnB4HtdM5JkFOs7rk4T5uxWa2QB%2Bxrb0uGWp6C%2FKniuq6eBMiJ59EW8Qua9SC1HjapOsfuus9g5HoQTBdya%2B%2B93vPUyT1l6n3DvNF79aTePLdf4GzCoc3La3CqQwXZ%2Bv00XVVkSLXyHqEtn%2BKj4RqGYDx5vybmCYgNtuQnt%2F4u%2FKij1yfRzcl%2BKOheRiB2UBQBFkx%2BGRL%2BqBFLx23kYZU2PrVD4ZjQMMXyglfn7R41W1Ts944jcTs7eKtPEaIuwbGZFi3rfxU%2BBL%2BrhXsqDJMbPTE%2BrqYpk6xiwMVJaY6kJH62kCLazVZrQ49cjhJjxeJti4aqVRxjr4XOP%2FJ9EatP%2BZoD3q47yNzrS1dG3FcQOp6Rtx1LGD9QPU8GrLpoB2%2F%2BrydWuCVqCFWw5iNbyp05sWQsfmSpFEMzsvkKO%2FCw0bATpkHdkF6WOn0A1lXIOsI0cDUPAe1xWJ3L0KZySQ0UZUqXJ8Gw4v%2FTlL5BY%2FUxSnor26xYwn6aO6wU6tAHBqopuW5pcz%2FJI%2BrCyUdYGVL8ZGUcN9osxZNHlsdHl%2FPSb5Ey3HqdiHTks1pszrFK8F0ZxsQNCYajkgKT3SAzhgrTmaNYfXyzLVkl3rMbW5QA0SqgsnR79JfHgUXuHGBnWyrsVF5mu9vmFjpTB4j2VqmtMOIjghMdHO%2FOIcR59ey2VTJQKE1Ulq0WJqECO72nl8nHMFEUoBLcWlCu5cwJlo5NxAcL7qC1hNPBzJlNFYMqU07s%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090752Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTY5J43SP76%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=41d5423206e9b4da9d8bad5f7023e4f96b18b2664c923fbc9de439a7f34293c4&hash=218a0f350491d1c5c383f9505b728b13f7879d7491bb1fb18a042fb95213e569&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S1359644616302513&tid=spdf-4c8cdfd3-7d8d-4705-a232-8bf4948ce6eb&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2016}, abtract = {The ‘form follows function’ principle implies that a structural determination of protein structures is indispensable to understand proteins in their biological roles. However, experimental methods still show shortcomings in the description of the dynamic properties of proteins. Therefore, molecular dynamics (MD) simulations represent an essential tool for structural biology to investigate proteins as flexible and dynamic entities. Here, we will give an overview on the impact of MD simulations on structural investigations, including studies that aim at a prediction of protein-folding pathways, protein-assembly processes and the sampling of conformational space by computational means.}, type = {Journal Article}, }

[120]

A. Bock, M. Bermudez, F. Krebs, C. Matera, B. Chirinda, D. Sydow, C. Dallanoce, U. Holzgrabe, M. De Amici, M. J. Lohse, G. Wolber, and K. Mohr. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor, J Biol Chem, 291(31):16375-16389, 2016.
Links: [doi:10.1074/jbc.M116.735431] [show BibTeX]  x  @article{RN197, author = {Bock, Andreas and Bermudez, Marcel and Krebs, Fabian and Matera, Carlo and Chirinda, Brian and Sydow, Dominique and Dallanoce, Clelia and Holzgrabe, Ulrike and De Amici, Marco and Lohse, Martin J. and Wolber, Gerhard and Mohr, Klaus}, title = {Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor}, journal = {Journal of Biological Chemistry}, volume = {291}, number = {31}, pages = {16375-16389}, DOI = {10.1074/jbc.M116.735431}, url = {http://www.jbc.org/content/291/31/16375.abstract http://www.jbc.org/content/291/31/16375.full.pdf}, year = {2016}, abtract = {G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.}, type = {Journal Article}, keywords = {gpcr} }

[119]

S. Bock, M. S. Murgueitio, G. Wolber, and G. Weindl. Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement, Pharmacol Res, 105:44-53, 2016.
Links: [doi:10.1016/j.phrs.2016.01.016] [show BibTeX]  x  @article{RN183, author = {Bock, Stephanie and Murgueitio, Manuela S. and Wolber, Gerhard and Weindl, Günther}, title = {Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1 polarization upon TLR2 engagement}, journal = {Pharmacological Research}, volume = {105}, pages = {44-53}, ISSN = {1043-6618}, DOI = {10.1016/j.phrs.2016.01.016}, url = {http://www.sciencedirect.com/science/article/pii/S1043661816000220}, year = {2016}, abtract = {Langerhans cells (LCs) represent a highly specialized subset of epidermal dendritic cells (DCs), yet not fully understood in their function of balancing skin immunity. Here, we investigated in vitro generated Langerhans-like cells obtained from the human acute myeloid leukaemia cell line MUTZ-3 (MUTZ-LCs) to study TLR- and cytokine-dependent activation of epidermal DCs. MUTZ-LCs revealed high TLR2 expression and responded robustly to TLR2 engagement, confirmed by increased CD83, CD86, PD-L1 and IDO expression, upregulated IL-6, IL-12p40 and IL-23p19 mRNA levels IL-8 release. TLR2 activation reduced CCR6 and elevated CCR7 mRNA expression and induced migration of MUTZ-LCs towards CCL21. Similar results were obtained by stimulation with pro-inflammatory cytokines TNF-α and IL-1β whereas ligands of TLR3 and TLR4 failed to induce a fully mature phenotype. Despite limited cytokine gene expression and production for TLR2-activated MUTZ-LCs, co-culture with naive CD4+ T cells led to significantly increased IFN-γ and IL-22 levels indicating Th1 differentiation independent of IL-12. TLR2-mediated effects were blocked by the putative TLR2/1 antagonist CU-CPT22, however, no selectivity for either TLR2/1 or TLR2/6 was observed. Computer-aided docking studies confirmed non-selective binding of the TLR2 antagonist. Taken together, our results indicate a critical role for TLR2 signalling in MUTZ-LCs considering the leukemic origin of the generated Langerhans-like cells.}, type = {Journal Article}, keywords = {Acute myeloid leukaemia (AML) Langerhans cells Toll-like receptors (TLR) TLR2 Pro-inflammatory cytokines T helper type 1 (Th1) cells} }

[118]

E. Guerrieri, M. Bermudez, G. Wolber, I. P. Berzetei-Gurske, H. Schmidhammer, and M. Spetea. Structural determinants of diphenethylamines for interaction with the κ opioid receptor: Synthesis, pharmacology and molecular modeling studies, Bioorg Med Chem Lett, 26(19):4769-4774, 2016.
Links: [doi:10.1016/j.bmcl.2016.08.031] [show BibTeX]  x  @article{RN191, author = {Guerrieri, Elena and Bermudez, Marcel and Wolber, Gerhard and Berzetei-Gurske, Ilona P. and Schmidhammer, Helmut and Spetea, Mariana}, title = {Structural determinants of diphenethylamines for interaction with the κ opioid receptor: Synthesis, pharmacology and molecular modeling studies}, journal = {Bioorganic & Medicinal Chemistry Letters}, volume = {26}, number = {19}, pages = {4769-4774}, ISSN = {0960-894X}, DOI = {10.1016/j.bmcl.2016.08.031}, url = {http://www.sciencedirect.com/science/article/pii/S0960894X16308526 https://pdf.sciencedirectassets.com/271398/1-s2.0-S0960894X16X00182/1-s2.0-S0960894X16308526/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJGMEQCIBSuXR284U5c9bmAJSN5zVw47n5M5VTNwrBmGQ8hLXVcAiAWIgoCDAYq%2BrLMnoeOj0gcwMsJ%2BK2%2F2vx37jlwfG9V%2FiraAwhBEAIaDDA1OTAwMzU0Njg2NSIMjEBFMn9jIE9t1XN2KrcDLe7GRG%2FXcw3WEgKV9YXbSGYcHYB2z7r%2B9eRerOT0zpE0wRSFgQ%2FOH9BXlp37MIlzoDaMcVajFKZS8gcJXSICZZRdMHztkVCBW4DNZa%2BJxOwJ1E6Q6vzyyBGsc%2FRoV6Xba79A94ndoN8bYy6WNuplWyrl3mWsK2vv7sI6kqAQYvwZAuSo66P%2FLefOdgACsLXUvDUtMMpSN8TmoE6MAFh%2Fj9u1tN2PHd7Si9U0lR%2BPybWjyQIZhRLaPFiPA459dq%2F0DJYDW6PUXjnBlCqj2pjkDd8G%2FcrPGVCvjIs1dEukqNYRPh9wSQFFAb5Fi0wZV3zG%2F46Hc%2FeUQIprBOrsYtxFvQ1UWxSkaVfuuRD2NfJJC%2FoyWTyuxNmD0bdhukh9A21%2B1W83wJfu%2FecDVcxhN9MqXTDLroqrvl%2BRxWFnb%2BWbs%2B%2FV9bgL2cBI6AFt4X60UAEM%2FPSuYh%2FCMbaK1dtKiQLD4N%2F7kxQrpF%2BWzb6z4YOF5hW%2F4Jm%2BgH%2B0v9v9lego%2FcMGf98VdcRdShnMV0057mzmxPdKDL4AivAyKRRfnHrHbLoO1SdPlc41DKXR%2BjK0GtocjZ5j4aUAxDDnpo7rBTq1AThXMgqWLXhCysjiDb69KUDsmtirRuTrXpezLGPDfxkFp5ofIqWUR9J0yQNBLS%2BqlghqmfiGup4DJm90ED%2Bjr269Tuc2Ri4J0zfr7%2BcI1xixL%2Fy0rAQI30TJNbf1CsDGxfVixVDBG1Fkwa3KlpjjfAGAuGKaiPkPOMJuLo8YTbs28PVbbZSstkpcNX0npq661wJ6SM3c0BNDLzt2HCCzsKCoWT8MzDtnFnmY8Er2Z7ayg87lxx0%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090730Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYZNRZYJFV%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=037fa3ee2555131e64b8b5688e7e4a686e30cbef207e6458fb55f96764b245fb&hash=08167983ee3f84a7da97f9261f1c7a8c6d2025de5b3aa82b896df1eb7cd149b2&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0960894X16308526&tid=spdf-8f3d8366-6e13-4767-a6f4-96592d64c57f&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2016}, abtract = {The κ opioid (KOP) receptor crystal structure in an inactive state offers nowadays a valuable platform for inquiry into receptor function. We describe the synthesis, pharmacological evaluation and docking calculations of KOP receptor ligands from the class of diphenethylamines using an active-like structure of the KOP receptor attained by molecular dynamics simulations. The structure–activity relationships derived from computational studies was in accordance with pharmacological activities of targeted diphenethylamines at the KOP receptor established by competition binding and G protein activation in vitro assays. Our analysis identified that agonist binding results in breaking of the Arg156-Thr273 hydrogen bond, which stabilizes the inactive receptor conformation, and a crucial hydrogen bond with His291 is formed. Compounds with a phenolic 4-hydroxy group do not form the hydrogen bond with His291, an important residue for KOP affinity and agonist activity. The size of the N-substituent hosted by the hydrophobic pocket formed by Val108, Ile316 and Tyr320 considerably influences binding and selectivity, with the n-alkyl size limit being five carbon atoms, while bulky substituents turn KOP agonists in antagonists. Thus, combination of experimental and molecular modeling strategies provides an initial framework for understanding the structural features of diphenethylamines that are essential to promote binding affinity and selectivity for the KOP receptor, and may be involved in transduction of the ligand binding event into molecular changes, ultimately leading to receptor activation.}, type = {Journal Article}, keywords = {κ opioid receptor Diphenethylamine Agonist Antagonist Partial agonist SAR Molecular dynamics gpcr} }

[117]

J. R. Homoki, A. Nemes, E. Fazekas, G. Gyémánt, P. Balogh, F. Gál, J. Al-Asri, J. Mortier, G. Wolber, L. Babinszky, and J. Remenyik. Anthocyanin composition, antioxidant efficiency, and α-amylase inhibitor activity of different Hungarian sour cherry varieties (Prunus cerasus L.), Food Chem, 194:222-229, 2016.
Links: [doi:10.1016/j.foodchem.2015.07.130] [show BibTeX]  x  @article{RN177, author = {Homoki, Judit R. and Nemes, Andrea and Fazekas, Erika and Gyémánt, Gyöngyi and Balogh, Péter and Gál, Ferenc and Al-Asri, Jamil and Mortier, Jérémie and Wolber, Gerhard and Babinszky, László and Remenyik, Judit}, title = {Anthocyanin composition, antioxidant efficiency, and α-amylase inhibitor activity of different Hungarian sour cherry varieties (Prunus cerasus L.)}, journal = {Food Chemistry}, volume = {194}, pages = {222-229}, ISSN = {0308-8146}, DOI = {10.1016/j.foodchem.2015.07.130}, url = {http://www.sciencedirect.com/science/article/pii/S0308814615011644 http://ac.els-cdn.com/S0308814615011644/1-s2.0-S0308814615011644-main.pdf?_tid= 626cf250-a00c-11e5-9e98-00000aacb35d&acdnat=1449841255_9edc44dca9e7c73085280f5fd716d846}, year = {2016}, abtract = {Five Hungarian sour cherry cultivars were studied to determine their anthocyanin contents and their possible inhibitory properties. The water and methanol soluble antioxidant capacities were separately assessed by photoluminescence showing values ranged from 3.4 μg mg−1 to 15.4 μg mg−1, respectively. The “VN1” variety (selected from “CsengÅ‘di csokros”) showed the highest antioxidant capacity. The anthocyanin content, measured by pH differential method or isolated by solid phase extraction, was the highest also in “VN1”. Correlation was found between the anthocyanin content and the high antioxidant capacity. The main anthocyanin components were cyanidin-3-O-rutinoside and cyanidin-3-O-glucoside. The presence of malvidin-3,5-O-diglycoside was verified by MALDI-TOF MS. Sour cherry extracts and selected anthocyanins inhibited the human salivary alpha-amylase catalyzed hydrolysis competitively. The lowest IC50 value, 55 μg mL−1 or 80 μM, was measured for malvidin-3,5-O-diglycoside, for which possible binding modes within the alpha-amylase active site could be investigated in silico using molecular docking and molecular dynamics.}, type = {Journal Article}, keywords = {Sour cherry Antioxidants Anthocyanins Human salivary α-amylase Inhibition} }

[116]

S. Köhling, G. Künze, K. Lemmnitzer, M. Bermudez, G. Wolber, J. Schiller, D. Huster, and J. Rademann. Chemoenzymatic Synthesis of Nonasulfated Tetrahyaluronan with a Paramagnetic Tag for Studying Its Complex with Interleukin-10, Chemistry - A European Journal, 22(16): 5563-5574, 2016.
Links: [doi:10.1002/chem.201504459] [show BibTeX]  x  @article{RN184, author = {Köhling, Sebastian and Künze, Georg and Lemmnitzer, Katharina and Bermudez, Marcel and Wolber, Gerhard and Schiller, Jürgen and Huster, Daniel and Rademann, Jörg}, title = {Chemoenzymatic Synthesis of Nonasulfated Tetrahyaluronan with a Paramagnetic Tag for Studying Its Complex with Interleukin-10}, journal = {Chemistry - A European Journal}, volume = {22}, number = {16}, pages = { 5563-5574}, ISSN = {1521-3765}, DOI = {10.1002/chem.201504459}, url = {http://dx.doi.org/10.1002/chem.201504459 http://onlinelibrary.wiley.com/store/10.1002/chem.201504459/asset/chem201504459.pdf?v= 1&t=ili6eox1&s=58b1d54b76bcf28cf8559dcb069e2abdebc61887}, year = {2016}, abtract = {Implants and artificial biomaterials containing sulfated hyaluronans have been shown to improve the healing of injured skin and bones. It is hypothesized that these effects are mediated by the binding of sulfated glycosaminoglycans (GAGs) to growth factors and cytokines, resulting in the sequestering of proteins to the wound healing site and in modulated protein activity. Given that no direct synthetic access to sulfated oligohyaluronans has been available, little is known about their protein binding and the structure of the resulting protein complexes. Here, the chemoenzymatic preparation of oligohyaluronans on the gram scale is described. Oligohyaluronans are converted into anomeric azides at the reducing end, enabling the attachment of analytical labels through an anomeric ligation reaction. A nonasulfated tetrahyaluronan–ethylenediaminetetraacetic acid derivative has been produced and used as a paramagnetic tag for the elucidation of the complex of this ligand with interleukin-10 using paramagnetic relaxation enhancement NMR analysis. The metal ion position is resolved with 1.0 Å, enabling a refined structural model of the complex.}, type = {Journal Article}, keywords = {carbohydrates cytokines growth factors host–guest systems protein structures} }

[115]

B. Nizami, D. Sydow, G. Wolber, and B. Honarparvar. Molecular insight on the binding of NNRTI to K103N mutated HIV-1 RT: molecular dynamics simulations and dynamic pharmacophore analysis, Mol Biosyst, 12:3385-3395, 2016.
Links: [doi:10.1039/C6MB00428H] [show BibTeX]  x  @article{RN196, author = {Nizami, Bilal and Sydow, Dominique and Wolber, Gerhard and Honarparvar, Bahareh}, title = {Molecular insight on the binding of NNRTI to K103N mutated HIV-1 RT: molecular dynamics simulations and dynamic pharmacophore analysis}, journal = {Molecular BioSystems}, volume = {12}, pages = {3385-3395}, DOI = {10.1039/C6MB00428H}, url = {https://pubs.rsc.org/en/content/articlepdf/2016/mb/c6mb00428h}, year = {2016}, type = {Journal Article}, }

[114]

V. Obermoser, M. E. Urban, M. S. Murgueitio, G. Wolber, U. Kintscher, and R. Gust. New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile, Eur J Med Chem, 124:138-152, 2016.
Links: [doi:10.1016/j.ejmech.2016.08.027] [show BibTeX]  x  @article{RN194, author = {Obermoser, Victoria and Urban, Margarethe E. and Murgueitio, Manuela S. and Wolber, Gerhard and Kintscher, Ulrich and Gust, Ronald}, title = {New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile}, journal = {European Journal of Medicinal Chemistry}, volume = {124}, pages = {138-152}, ISSN = {0223-5234}, DOI = {10.1016/j.ejmech.2016.08.027}, url = {http://www.sciencedirect.com/science/article/pii/S0223523416306705 https://pdf.sciencedirectassets.com/271932/1-s2.0-S0223523416X00165/1-s2.0-S0223523416306705/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJn%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBfvzJJhZ1Mm5mwy0J3B5VMuELdFjoz7sIRqN8wYSzx3AiEA5SeL7MgEjFO0B9r5FrlpUN4T0hArwMRoS5vGU9JFDzkq2gMIQhACGgwwNTkwMDM1NDY4NjUiDBOT17U1MUqycs1%2FKCq3AxGHFD6W1QLBSzH%2FhBU3v8JJteKuM%2BMlhBDgx9HJr06UFb8BZd%2BHmmbs1ur5t%2FlqtRCT5APQ%2Fzl6M%2FIM8%2F6YwmMYXt9Jyw268%2FtZeBsyIAjhb9UY49j0c7v6aVzNad%2FGYTpVso5RHp%2FRIuM5L67h7pTwnakyTSI6BnpaJqI2B9kWP4JEsZprxWxTmvQw9wKd%2BZ%2Fa4mZjyJSBse7DFly8%2FGnCKXIXFbkL7gEHIAamV19AyDb7zMu0NjKSYkVhnMKdyKtcoydss0kNGXNm7HiEVwqeBYZLCKy4Gr96z9kBNqkcZ%2BCvqAOmMj10aPUlpkLbmx197FcTVJ8VImn9RLlCJRDmDXNX5yS0%2B73PI%2BEazQ5%2BwF1N29hqIzLnT1Cc5utmeZ0G5AMefCBRfmgg6E2TbmfR7Ww0V5jCzNNuAslQXXlpfPN3WJ9keKLw21X%2BSCqBPm%2Fu6Xis2DUor4OC8wohPM2ZjGByx3Gqx2LFJIPCZN3cJyL1gxaivo%2BET3s3jVm6OY0z8nVa20tLJ7Fw2PK6UzrCG3VQ%2F1Wx6deq5BIg0CjfaQgBifcwYqv%2F%2F9ZMxV6ugcNNvcoHxYgw6rmO6wU6tAGkBGWe9a6585563qyrPRyFqAu%2FM2418LDCloFTRDRH9weZ%2BgHQW1B1m%2F%2FVbRWsTdBwvnU%2BOX7Dk7jsNsnZIzAffqBskxE32pvB9%2BEG%2Fi%2F0HR72BRBiQS0zSE42%2F3v4dfwbryhRJ%2FbSj6%2BtUzOYJwiXE%2BTFI6%2Bw6by7InD6OwR0E1IdegTjGtbvA15LPpug9CTJY%2FTVHEISFL2jcir2FrGkZbfPHhgSZLoAg3rn1UL%2Buq%2FcLM4%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090924Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYRDRFHOHF%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=d2af90fb06808e3b0bac76b9342ee55dc05a1918c4bf6356770302f3be9ca63a&hash=3712ce5d2ed3cc4cfea7455155afedf7877f1ff08f9c2449aca8649d1b47fa34&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S0223523416306705&tid=spdf-de97841d-cbf2-4767-9ef3-8519019df2d9&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2016}, abtract = {In previous studies, the 4′-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid was identified as pharmacophoric core for PPARγ activation. In this structure-activity relationship study the C2-alkyl chain was elongated and the 2-COOH group was changed to a carbamide/nitrile or shifted to the 3- or 4-position. Furthermore, the benzo[d]imidazole was exchanged by 2,3-dihydrobenzo[d]thiazole or 1H-indole. C2-propyl derivatives showed the profile of partial agonists, while elongation of the C2-chain to that of an n-heptyl group or a 4-COOH shift changed the pharmacological profile to that of a potent full agonist. This finding can be explained by binding to the LBD in different ligand conformations. Two anchoring points (Tyr473 and Arg288) exist in the LBD, which have to be contacted to achieve receptor activation. In a crystal violet chemosensitivity assay using COS-7 cells and LNCaP cells expressing PPARγ only the carboxamide derivatives influenced the cell growth, independently on the presence of the PPARγ. Therefore, receptor mediated cytotoxicity can be excluded.}, type = {Journal Article}, keywords = {PPARγ Transactivation Cytotoxicity Binding mode Molecular modeling} }

[113]

C. Rakers, F. Schumacher, W. Meinl, H. Glatt, B. Kleuser, and G. Wolber. In silico prediction of human sulfotransferase 1E1 activity guided by pharmacophores from molecular dynamics simulations, J Biol Chem, 291(1):58-71, 2016.
Links: [doi:10.1074/jbc.M115.685610] [show BibTeX]  x  @article{RN180, author = {Rakers, Christin and Schumacher, Fabian and Meinl, Walter and Glatt, Hansruedi and Kleuser, Burkhard and Wolber, Gerhard}, title = {In silico prediction of human sulfotransferase 1E1 activity guided by pharmacophores from molecular dynamics simulations}, journal = {Journal of Biological Chemistry}, volume = {291}, number = {1}, pages = {58-71}, DOI = {10.1074/jbc.M115.685610}, url = {http://www.jbc.org/content/early/2015/11/05/jbc.M115.685610.abstract http://www.jbc.org/content/early/2015/11/05/jbc.M115.685610.full.pdf}, year = {2016}, abtract = {Acting during phase II metabolism, sulfotransferases (SULTs) serve detoxification by transforming a broad spectrum of compounds from pharmaceutical, nutritional, or environmental sources into more easily excretable metabolites. However, SULT activity has also been shown to promote formation of reactive metabolites that may have genotoxic effects. SULT subtype 1E1 (SULT1E1) was identified as a key player in estrogen homeostasis, which is involved in many physiological processes and the pathogenesis of breast and endometrial cancer. The development of an in silico prediction model for SULT1E1 ligands would therefore support the development of metabolically inert drugs and help to assess health risks related to hormonal imbalances. Here, we report on a novel approach to develop a model that enables prediction of substrates and inhibitors of SULT1E1. Molecular dynamics simulations were performed to investigate enzyme flexibility and sample protein conformations. Pharmacophores were developed that served as a cornerstone of the model and machine learning techniques were applied for prediction refinement. The prediction model was used to screen the DrugBank (a database of experimental and approved drugs): 28 % of the predicted hits were reported in literature as ligands of SULT1E1. From the remaining hits, a selection of nine molecules was subjected to biochemical assay validation and experimental results were in accordance with the in silico prediction of SULT1E1 inhibitors and substrates, thus affirming our prediction hypotheses.}, type = {Journal Article}, }

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2015

[112]

J. Al-Asri, E. Fazekas, G. Lehoczki, A. Perdih, C. Görick, M. F. Melzig, G. Gyémánt, G. Wolber, and J. Mortier. From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors, Bioorg Med Chem, 23(20):6725-6732, 2015.
Links: [doi:10.1016/j.bmc.2015.09.007] [show BibTeX]  x  @article{RN181, author = {Al-Asri, Jamil and Fazekas, Erika and Lehoczki, Gábor and Perdih, Andrej and Görick, Cornelia and Melzig, Matthias F. and Gyémánt, Gyöngyi and Wolber, Gerhard and Mortier, Jérémie}, title = {From carbohydrates to drug-like fragments: Rational development of novel α-amylase inhibitors}, journal = {Bioorganic & Medicinal Chemistry}, volume = {23}, number = {20}, pages = {6725-6732}, ISSN = {0968-0896}, DOI = {10.1016/j.bmc.2015.09.007}, url = {http://www.sciencedirect.com/science/article/pii/S0968089615300304 http://ac.els-cdn.com/S0968089615300304/1-s2.0-S0968089615300304-main.pdf?_tid= 975ce9ee-a00b-11e5-8116-00000aab0f6b&acdnat=1449840915_65cd6dd9bfdd7bab4bc7170cedef1f08}, year = {2015}, abtract = {Starch catabolism leading to high glucose level in blood is highly problematic in chronic metabolic diseases, such as type II diabetes and obesity. α-Amylase catalyzes the hydrolysis of starch, increasing blood sugar concentration. Its inhibition represents a promising therapeutic approach to control hyperglycaemia. However, only few drug-like molecule inhibitors without sugar moieties have been discovered so far, and little information on the enzymatic mechanism is available. This work aims at the discovery of novel small α-amylase binders using a systematic in silico methodology. 3D-pharmacophore-based high throughput virtual screening of small compounds libraries was performed to identify compounds with high α-amylase affinity. Twenty-seven compounds were selected and biologically tested, revealing IC50 values in the micromolar range and ligand efficiency higher than the one of the bound form of acarbose, which is used as a reference for α-amylase inhibition.}, type = {Journal Article}, keywords = {α-Amylase inhibition Fragment-based drug design Virtual screening Pharmacophore model Hyperglycaemia Obesity Type II diabetes} }

[111]

M. Bermudez, C. Rakers, and G. Wolber. Structural characteristics of the allosteric binding site represent a key to subtype selective modulators of muscarinic acetylcholine receptors, Mol Inf, 34(8):526-530, 2015.
Links: [doi:10.1002/minf.201500025] [show BibTeX]  x  @article{RN178, author = {Bermudez, Marcel and Rakers, Christin and Wolber, Gerhard}, title = {Structural characteristics of the allosteric binding site represent a key to subtype selective modulators of muscarinic acetylcholine receptors}, journal = {Molecular Informatics}, volume = {34}, number = {8}, pages = {526-530}, ISSN = {1868-1751}, DOI = {10.1002/minf.201500025}, url = {http://dx.doi.org/10.1002/minf.201500025 http://onlinelibrary.wiley.com/store/10.1002/minf.201500025/asset/526_ftp.pdf?v= 1&t=ii1pqq6x&s=d5a558605b40783fdaa53e4c2a054424c9266926}, year = {2015}, abtract = {The high conservation of the orthosteric acetylcholine binding site of muscarinic receptors (MAChR) represents a considerable challenge in terms of designing subtype selective drugs. A promising approach to gain subtype selectivity is to include allosteric or dualsteric targeting that aims to address more specific extracellular binding sites. Despite recent advances in crystallography of G protein coupled receptors (GPCRs), structural information for all 5 MAChR subtypes is not yet available. Here we report structural models of the active and the inactive receptor state of all subtypes derived by homology modelling in combination with MD simulations. The comparison of the allosteric binding site unveils the characteristics for each subtype on a structural level and indicates anchor points for rational design of selective drugs. Additionally, homology models offer the possibility for a rational explanation of dualsteric subtype selectivity, as we show for the M2 over M5 selectivity of the dualsteric ligands Atr-6-naph and Iper-6-phth.}, type = {Journal Article}, keywords = {Drug design Medicinal chemistry Molecular dynamics Protein models Receptors gpcr} }

[110]

M. Bermudez, and G. Wolber. Structure vs. function - the impact of computational methods on the discovery of specific GPCR-ligands, Bioorg Med Chem, 23(14):3907-3912, 2015.
Links: [doi:10.1016/j.bmc.2015.03.026] [show BibTeX]  x  @article{RN171, author = {Bermudez, Marcel and Wolber, G.}, title = {Structure vs. function - the impact of computational methods on the discovery of specific GPCR-ligands}, journal = {Bioorganic & Medicinal Chemistry}, volume = {23}, number = {14}, pages = {3907-3912}, DOI = {10.1016/j.bmc.2015.03.026}, url = {http://ac.els-cdn.com/S0968089615002102/1-s2.0-S0968089615002102-main.pdf?_tid=94b05366-a00b-11e5-866f-00000aacb35f&acdnat=1449840910_d9e103adde14b947c8c62833dffbd577}, year = {2015}, abtract = {Over the past decades, computational methods have become invaluable for drug design campaigns but also as auxiliary tool for structural biology. The combination of experimental and in silico methods in the field of G protein coupled receptors (GPCRs) is indispensable. Despite recent groundbreaking achievements in GPCR crystallography, structural information for the vast majority of this physiologically important protein class is only accessible through homology models. Since the understanding of the conformational changes resulting in multiple activation pathways is incomplete, the design of specific GPCR modulating drugs remains a major challenge. However, due to the highly interdisciplinary requirements for the investigation of receptor function and the necessity of joining scientist from different fields, computational approaches gain importance in rationalizing and illustrating certain specific effects. In silico methods, such as molecular dynamics (MD) simulations, pharmacophore modeling or docking, proved to be suitable to complement experimental approaches. In this review, we highlight recent examples of in silico studies that were successfully applied in the field of GPCR research. Those approaches follow two main goals: Firstly, structural investigations that help to understand the receptor function and the characterization of ligand binding and secondly the identification of novel GPCR modulators as potential drugs.}, type = {Journal Article}, keywords = {gpcr} }

[109]

R. B. El-Houri, D. E. Kotowska, K. B. Christensen, S. Bhattacharya, N. Oksbjerg, G. Wolber, K. Kristiansen, and L. P. Christensen. Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes, Food and Function, 6(7):2135-44, 2015.
Links: [doi:10.1039/C5FO00223K] [show BibTeX]  x  @article{RN175, author = {El-Houri, Rime Bahij and Kotowska, Dorota Ewa and Christensen, Kathrine Bisgaard and Bhattacharya, Sumangala and Oksbjerg, Niels and Wolber, Gerhard and Kristiansen, Karsten and Christensen, Lars Porskjær}, title = {Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes}, journal = {Food and Function}, volume = {6}, number = {7}, pages = {2135-44}, DOI = {10.1039/C5FO00223K}, url = {http://pubs.rsc.org/en/content/articlepdf/2015/fo/c5fo00223k}, year = {2015}, abtract = {A dichloromethane (DCM) extract of carrot roots was found to stimulate insulin-dependent glucose uptake (GU) in adipocytes in a dose dependent manner. Bioassay-guided fractionation of the DCM extract resulted in the isolation of the polyacetylenes falcarinol and falcarindiol. Both polyacetylenes were able to significantly stimulate basal and/or insulin-dependent GU in 3T3-L1 adipocytes and porcine myotube cell cultures in a dose-dependent manner. Falcarindiol increased peroxisome proliferator-activated receptor (PPAR)γ-mediated transactivation significantly at concentrations of 3, 10 and 30 μM, while PPARγ-mediated transactivation by falcarinol was only observed at 10 μM. Docking studies accordingly indicated that falcarindiol binds to the ligand binding domain of PPARγ with higher affinity than falcarinol and that both polyacetylenes exhibit characteristics of PPARγ partial agonists. Falcarinol was shown to inhibit adipocyte differentiation as evident by gene expression studies and Oil Red O staining, whereas falcarindiol did not inhibit adipocyte differentiation, which indicates that these polyacetylenes have distinct modes of action. The results of the present study suggest that falcarinol and falcarindiol may represent scaffolds for novel partial PPARγ agonists with possible antidiabetic properties.}, type = {Journal Article}, }

[108]

R. B. El-Houri, J. Mortier, M. S. Murgueitio, G. Wolber, and L. P. Christensen. Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches, Planta Med, 81(06):488-494, 2015.
Links: [doi:10.1055/s-0034-1383119] [show BibTeX]  x  @article{RN151, author = {El-Houri, Rime B. and Mortier, Jérémie and Murgueitio, Manuela S. and Wolber, Gerhard and Christensen, Lars P.}, title = {Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches}, journal = {Planta Med}, volume = {81}, number = {06}, pages = {488-494}, ISSN = {0032-0943}, DOI = {10.1055/s-0034-1383119}, url = {https://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0034-1383119.pdf}, year = {2015}, abtract = {Peroxisome proliferator-activated receptor γ plays an important role in lipid and glucose homeostasis and is the target of many drug discovery investigations because of its role in diseases such as type 2 diabetes. Activation of peroxisome proliferator-activated receptor γ by agonists leads to a conformational change in the ligand-binding domain altering the transcription of several target genes involved in glucose and lipid metabolism, resulting in, for example, facilitation of glucose and lipid uptake and amelioration of insulin resistance, and other effects that are important in the treatment of type 2 diabetes. Peroxisome proliferator-activated receptor γ partial agonists are compounds with diminished agonist efficacy compared to full agonists; however, they maintain the antidiabetic effect of full agonists but do not induce the same magnitude of side effects. This mini-review gives a short introduction to in silico screening methods and recent research advances using computational approaches to identify peroxisome proliferator-activated receptor γ agonists, especially partial agonists, from natural sources and how these ligands bind to the peroxisome proliferator-activated receptor γ in order to better understand their biological effects.}, type = {Journal Article}, }

[107]

S. Grosskopf, C. Eckert, C. Arkona, S. Radetzki, K. Böhm, U. Heinemann, G. Wolber, J. v. Kries, W. Birchmeier, and J. Rademann. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in-vitro and in-vivo, ChemMedChem, 10(5):815-826, 2015.
Links: [doi:10.1002/cmdc.201500015] [show BibTeX]  x  @article{RN172, author = {Grosskopf, Stefanie and Eckert, Chris and Arkona, Christoph and Radetzki, Silke and Böhm, Kerstin and Heinemann, Udo and Wolber, Gerhard and Kries, Jens-Peter von and Birchmeier, Walter and Rademann, Jörg}, title = {Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in-vitro and in-vivo}, journal = {Chemmedchem}, volume = {10}, number = {5}, pages = {815-826}, DOI = {10.1002/cmdc.201500015}, url = {http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201500015/abstract https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201500015}, year = {2015}, abtract = {Selective inhibitors of the protein tyrosine phosphatase SHP2 (PTPN11), an enzyme, deregulated in numerous human tumors, were generated by combination of chemical synthesis with structure-based rational design. 70 pyridazolon-4-ylidene-hydrazinyl-benzene sulfonates were prepared and evaluated in enzyme assays. Binding modes of active inhibitors were simulated in silico using a newly generated crystal structure of SHP2. The most powerful molecule 25 (GS-493) inhibited SHP2 with an IC50 value of 71 ± 15 nM in the enzyme assay and was 29- and 45-fold more active than against related SHP1 and PTP1B. In cell culture experiments 25 blocked HGF-stimulated epithelial-mesenchymal transition of human pancreatic tumor cells HPAF as indicated by the reduction of minimum neighbor distances of cells. Moreover, 25 inhibited cell colony formation of the non-small cell lung cancer cell line LXFA 526L in soft agar. Finally, it inhibited tumor growth in a murine xenograft model. Thus, the novel specific molecule strengthens the hypothesis that SHP2 is a relevant protein target for the inhibition of mobility and invasiveness of cancer cells.}, type = {Journal Article}, }

[106]

C. Meinguet, C. Bruyère, R. Frédérick, V. Mathieu, C. Vancraeynest, L. Pochet, J. Laloy, J. Mortier, G. Wolber, R. Kiss, B. Masereel, and J. Wouters. 3D-QSAR, Design, Synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties, Eur J Med Chem, 94:45-55, 2015.
Links: [doi:10.1016/j.ejmech.2015.02.044] [show BibTeX]  x  @article{RN169, author = {Meinguet, Céline and Bruyère, Céline and Frédérick, Raphaël and Mathieu, Véronique and Vancraeynest, Christelle and Pochet, Lionel and Laloy, Julie and Mortier, Jérémie and Wolber, Gerhard and Kiss, Robert and Masereel, Bernard and Wouters, Johan}, title = {3D-QSAR, Design, Synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties}, journal = {European Journal of Medicinal Chemistry}, volume = {94}, pages = {45-55}, ISSN = {0223-5234}, DOI = {10.1016/j.ejmech.2015.02.044}, url = {http://www.sciencedirect.com/science/article/pii/S0223523415001403 http://ac.els-cdn.com/S0223523415001403/1-s2.0-S0223523415001403-main.pdf?_tid= f547ccae-c00a-11e4-8b31-00000aab0f01&acdnat=1425211582_cb6d118f6d7adec74c3f2a725b13dbdb}, year = {2015}, abtract = {Apolar trisubstituted derivatives of harmine show high antiproliferative activity on diverse cancer cell lines. However, these molecules present a poor solubility making these compounds poorly bioavailable. Here, new compounds were synthesized in order to improve solubility while retaining antiproliferative activity. First, polar substituents have shown a higher solubility but a loss of antiproliferative activity. Second, a Comparative Molecular Field Analysis (CoMFA) model was developed, guiding the design and synthesis of eight new compounds. Characterization has underlined the in vitro antiproliferative character of these compounds on five cancerous cell lines, combining with a high solubility at physiological pH, making these molecules druggable. Moreover, targeting glioma treatment, human intestinal absorption and blood brain penetration have been calculated, showing high absorption and penetration properties.}, type = {Journal Article}, keywords = {Harmine derivatives Antiproliferative activity Cytostatic activity Comparative Molecular Field Analysis} }

[105]

J. Mortier, E. K. Nyakatura, O. Reimann, S. Huhmann, J. O. Daldrop, C. Baldauf, G. Wolber, M. S. Miettinen, and B. Koksch. Coiled-Coils in Phage Display Screening: Insight into Exceptional Selectivity Provided by Molecular Dynamics, J Chem Inf Model, 55(3):495-500, 2015.
Links: [doi:10.1021/ci500689c] [show BibTeX]  x  @article{RN160, author = {Mortier, J. and Nyakatura, E. K. and Reimann, O. and Huhmann, S. and Daldrop, J. O. and Baldauf, C. and Wolber, G. and Miettinen, M. S. and Koksch, B.}, title = {Coiled-Coils in Phage Display Screening: Insight into Exceptional Selectivity Provided by Molecular Dynamics}, journal = {J Chem Inf Model}, volume = {55}, number = {3}, pages = {495-500}, ISSN = {1549-960X (Electronic) 1549-9596 (Linking)}, DOI = {10.1021/ci500689c}, url = {http://www.ncbi.nlm.nih.gov/pubmed/25648076 http://pubs.acs.org/doi/pdfplus/10.1021/ci500689c}, year = {2015}, abtract = {Involved in numerous key biological functions, protein helix-helix interactions follow a well-defined intermolecular recognition pattern. The characteristic structure of the alpha-helical coiled-coil allows for the specific randomization of clearly defined interaction partners within heteromeric systems. In this work, a rationally designed heterodimeric coiled-coil was used to investigate potential factors influencing the sequence selectivity in interhelical interactions.}, type = {Journal Article}, }

[104]

J. Mortier, C. Rakers, M. Bermudez, M. S. Murgueitio, S. Riniker, and G. Wolber. The impact of molecular dynamics on drug design: applications for the characterization of ligand-macromolecule complexes, Drug Discov Today, 20(6):686-702, 2015.
Links: [doi:10.1016/j.drudis.2015.01.003] [show BibTeX]  x  @article{RN162, author = {Mortier, J. and Rakers, C. and Bermudez, M. and Murgueitio, M. S. and Riniker, S. and Wolber, G.}, title = {The impact of molecular dynamics on drug design: applications for the characterization of ligand-macromolecule complexes}, journal = {Drug Discov Today}, volume = {20}, number = {6}, pages = {686-702}, ISSN = {1878-5832 (Electronic) 1359-6446 (Linking)}, DOI = {10.1016/j.drudis.2015.01.003}, url = {http://ac.els-cdn.com/S1359644615000215/1-s2.0-S1359644615000215-main.pdf?_tid=fd77aa3e-c00a-11e4-b562-00000aab0f6b&acdnat=1425211596_ad8df81890ab97631dd774ae4cbe1b41}, year = {2015}, abtract = {Among all tools available to design new drugs, molecular dynamics (MD) simulations have become an essential technique. Initially developed to investigate molecular models with a limited number of atoms, computers now enable investigations of large macromolecular systems with a simulation time reaching the microsecond range. The reviewed articles cover four years of research to give an overview on the actual impact of MD on the current medicinal chemistry landscape with a particular emphasis on studies of ligand-protein interactions. With a special focus on studies combining computational approaches with data gained from other techniques, this review shows how deeply embedded MD simulations are in drug design strategies and articulates what the future of this technique could be.}, type = {Journal Article}, keywords = {software} }

[103]

M. K. Parr, F. Botrè, A. Naß, J. Hengevoss, P. Diel, and G. Wolber. Ecdysteroids: A novel class of anabolic agents?, Biol Sport, 32(2):169-173, 2015.
Links: [doi:10.5604/20831862.1144420] [show BibTeX]  x  @article{RN170, author = {Parr, Maria Kristina and Botrè, Francesco and Naß, Alexandra and Hengevoss, Jonas and Diel, Patrick and Wolber, Gerhard}, title = {Ecdysteroids: A novel class of anabolic agents?}, journal = {Biol Sport}, volume = {32}, number = {2}, pages = {169-173}, DOI = {10.5604/20831862.1144420}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447764/pdf/JBS-32-1144420.pdf}, year = {2015}, abtract = {Increasing numbers of dietary supplements with ecdysteroids are marketed as "natural anabolic agents". Results of recent studies suggested that their anabolic effect is mediated by estrogen receptor (ER) binding. Within this study the anabolic potency of ecdysterone was compared to well characterized anabolic substances. Effects on the fiber sizes of the soleus muscle in rats as well the diameter of C2C12 derived myotubes were used as biological readouts. Ecdysterone exhibited a strong hypertrophic effect on the fiber size of rat soleus muscle that was found even stronger compared to the test compounds metandienone (dianabol), estradienedione (trenbolox), and SARM S 1, all administered in the same dose (5 mg/kg body weight, for 21 days). In C2C12 myotubes ecdysterone (1 uM) induced a significant increase of the diameter comparable to dihydrotestosterone (1 uM) and IGF 1 (1.3 nM). Molecular docking experiments supported the ERβ mediated action of ecdysterone. To clarify its status in sports, ecdysterone should be considered to be included in the class "S1.2 Other Anabolic Agents" of the list of prohibited substances of the World Anti-Doping Agency.}, type = {Journal Article}, }

[102]

A. Perdih, M. Hrast, K. Pureber, H. Barreteau, S. Grdadolnik, D. Kocjan, S. Gobec, T. Solmajer, and G. Wolber. Furan-based benzene mono- and dicarboxylic acid derivatives as multiple inhibitors of the bacterial Mur ligases (MurC-MurF): experimental and computational characterization, J Comput Aided Mol Des, :1-20, 2015.
Links: [doi:10.1007/s10822-015-9843-6] [show BibTeX]  x  @article{RN174, author = {Perdih, Andrej and Hrast, Martina and Pureber, Kaja and Barreteau, Hélène and Grdadolnik, SimonaGolič and Kocjan, Darko and Gobec, Stanislav and Solmajer, Tom and Wolber, Gerhard}, title = {Furan-based benzene mono- and dicarboxylic acid derivatives as multiple inhibitors of the bacterial Mur ligases (MurC-MurF): experimental and computational characterization}, journal = {Journal of Computer-Aided Molecular Design}, pages = {1-20}, ISSN = {0920-654X}, DOI = {10.1007/s10822-015-9843-6}, url = {http://dx.doi.org/10.1007/s10822-015-9843-6 http://download.springer.com/static/pdf/718/art%253A10.1007%252Fs10822-015-9843-6.pdf?originUrl= http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs10822-015-9843-6&token2=exp=1444917652~acl=%2Fstatic%2Fpdf%2F718%2Fart%25253A10.1007%25252Fs10822-015-9843-6.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs10822-015-9843-6*~hmac=4f2c8e6a70f3ecc9b08f6110e685bc18eddcae8b3233d8a3acaff9ac2b51bdc2}, year = {2015}, abtract = {Bacterial resistance to the available antibiotic agents underlines an urgent need for the discovery of novel antibacterial agents. Members of the bacterial Mur ligase family MurC-MurF involved in the intracellular stages of the bacterial peptidoglycan biosynthesis have recently emerged as a collection of attractive targets for novel antibacterial drug design. In this study, we have first extended the knowledge of the class of furan-based benzene-1,3-dicarboxylic acid derivatives by first showing a multiple MurC-MurF ligase inhibition for representatives of the extended series of this class. Steady-state kinetics studies on the MurD enzyme were performed for compound 1, suggesting a competitive inhibition with respect to ATP. To the best of our knowledge, compound 1 represents the first ATP-competitive MurD inhibitor reported to date with concurrent multiple inhibition of all four Mur ligases (MurC-MurF). Subsequent molecular dynamic (MD) simulations coupled with interaction energy calculations were performed for two alternative in silico models of compound 1 in the UMA/D-Glu- and ATP-binding sites of MurD, identifying binding in the ATP-binding site as energetically more favorable in comparison to the UMA/D-Glu-binding site, which was in agreement with steady-state kinetic data. In the final stage, based on the obtained MD data novel furan-based benzene monocarboxylic acid derivatives 8-11, exhibiting multiple Mur ligase (MurC-MurF) inhibition with predominantly superior ligase inhibition over the original series, were discovered and for compound 10 it was shown to possess promising antibacterial activity against S. aureus. These compounds represent novel leads that could by further optimization pave the way to novel antibacterial agents. }, type = {Journal Article}, keywords = {Bacterial Mur (MurC–MurF) ligase ATP-competitive inhibition Molecular dynamics (MD) Steady-state kinetics measurements Antibacterial agents Drug design} }

[101]

C. Rakers, M. Bermudez, B. G. Keller, J. Mortier, and G. Wolber. Computational close up on protein–protein interactions: how to unravel the invisible using molecular dynamics simulations?, WIREs Comput Mol Sci, 5(5):345-359, 2015.
Links: [doi:10.1002/wcms.1222] [show BibTeX]  x  @article{RN176, author = {Rakers, Christin and Bermudez, Marcel and Keller, Bettina G. and Mortier, Jérémie and Wolber, Gerhard}, title = {Computational close up on protein–protein interactions: how to unravel the invisible using molecular dynamics simulations?}, journal = {WIREs Comput Mol Sci}, volume = {5}, number = {5}, pages = {345-359}, DOI = {10.1002/wcms.1222}, url = {http://onlinelibrary.wiley.com/doi/10.1002/wcms.1222/abstract http://onlinelibrary.wiley.com/store/10.1002/wcms.1222/asset/wcms1222.pdf?v= 1&t=ii1ppzby&s=c5ce7829a968b92bb67ba6f3cc35285d70cee2ca}, year = {2015}, abtract = {As an essential part of many biological processes, protein–protein interactions (PPIs) offer exciting and promising opportunities for drug discovery by extension of the druggable target space. Over the last decade, studies on protein networks have significantly increased the number of identified PPIs. However, despite steadily growing data on PPIs, detailed understanding of the interaction surfaces and their dynamics remains limited. Furthermore, the development of small‐molecule inhibitors of PPIs faces technological challenges, leaving the question about the ‘druggability’ of PPIs open. Molecular dynamics (MD) simulations may facilitate the prediction of druggable binding sites on protein–protein interfaces by detecting binding hot spots and transient pockets. MD allows for a detailed analysis of structural and functional aspects of PPIs and thus provides valuable insights into PPI mechanisms and supports the design of PPI modulators. We provide an overview on the main areas of MD applications to PPIs including structural investigations and the design of PPI disruptors. Emphasizing the beneficial synergies between computational and experimental techniques, MD techniques are also frequently applied to low‐resolution structural data and have been used to elucidate structure and movements of complex macromolecular structures relevant for biological processes.}, type = {Journal Article}, }

[back to top]

2014 and earlier

[100]

V. Asante, J. Mortier, G. Wolber, and B. Koksch. Impact of fluorination on proteolytic stability of peptides: a case study with α-chymotrypsin and pepsin, Amino Acids, 46(12):2733-2744, 2014.
Links: [doi:10.1007/s00726-014-1819-7] [show BibTeX]  x  @article{RN147, author = {Asante, Vivian and Mortier, Jérémie and Wolber, Gerhard and Koksch, Beate}, title = {Impact of fluorination on proteolytic stability of peptides: a case study with α-chymotrypsin and pepsin}, journal = {Amino Acids}, volume = {46}, number = {12}, pages = {2733-2744}, ISSN = {0939-4451}, DOI = {10.1007/s00726-014-1819-7}, year = {2014}, abtract = {Protease stability is a key consideration in the development of peptide-based drugs. A major approach to increase the bioavailability of pharmacologically active peptides is the incorporation of non-natural amino acids. Due to the unique properties of fluorine, fluorinated organic molecules have proven useful in the development of therapeutically active small molecules as well as in materials and crop science. This study presents data on the ability of fluorinated amino acids to influence proteolytic stability when present in peptide sequences that are based on ideal protease substrates. Different model peptides containing fluorinated amino acids or ethylglycine in the P2, P1′or P2′ positions were designed according to the specificities of the serine protease, α-chymotrypsin (EC 3.4.21.1) or the aspartic protease, pepsin (EC 3.4.23.1). The proteolytic stability of the peptides toward these enzymes was determined by an analytical RP-HPLC assay with fluorescence detection and compared to a control sequence. Molecular modeling was used to support the interpretation of the structure–activity relationship based on the analysis of potential ligand-enzyme interactions. Surprisingly, an increase in proteolytic stability was observed only in a few cases. Thus, this systematic study shows that the proteolytic stability of fluorinated peptides is not predictable, but rather is a very complex phenomenon that depends on the particular enzyme, the position of the substitution relative to the cleavage site and the fluorine content of the side chain.}, type = {Journal Article}, keywords = {Chymotrypsin Pepsin Aminobutyric acid Difluoroethylglycine Trifluoroethylglycine} }

[99]

S. A. Galal, S. H. M. Khairat, F. A. F. Ragab, A. S. Abdelsamie, M. M. Ali, S. M. Soliman, J. Mortier, G. Wolber, and H. I. El Diwani. Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity, Eur J Med Chem, 86:122-132, 2014.
Links: [doi:10.1016/j.ejmech.2014.08.048] [show BibTeX]  x  @article{RN152, author = {Galal, Shadia A. and Khairat, Sarah H. M. and Ragab, Fatma A. F. and Abdelsamie, Ahmed S. and Ali, Mamdouh M. and Soliman, Salwa M. and Mortier, Jérémie and Wolber, Gerhard and El Diwani, Hoda I.}, title = {Design, synthesis and molecular docking study of novel quinoxalin-2(1H)-ones as anti-tumor active agents with inhibition of tyrosine kinase receptor and studying their cyclooxygenase-2 activity}, journal = {European Journal of Medicinal Chemistry}, volume = {86}, number = {0}, pages = {122-132}, ISSN = {0223-5234}, DOI = {10.1016/j.ejmech.2014.08.048}, url = {http://www.sciencedirect.com/science/article/pii/S0223523414007831 http://ac.els-cdn.com/S0223523414007831/1-s2.0-S0223523414007831-main.pdf?_tid= b482ad88-a00b-11e5-8f62-00000aacb361&acdnat=1449840963_a223020762d86fd4b9cb81d2db1509d5}, year = {2014}, abtract = {On continuation to our work, new quinoxalin-2(1H)-ones were synthesized to study their cytotoxic effect against HepG-2 and MCF-7 with their effect on the human tyrosine kinase (TRK). Compounds 12, 18, 15, 13, 11a, 20 and 16, respectively, were found to be more potent than cisplatin against HepG2 and selective to TRK. Also, compounds 12, 18, 20, 13, 14, and 22, respectively, exhibited decidedly activity against MCF-7 and selectivity against human TRK compared to cisplatin. A molecular docking study was also performed to gain comprehensive understanding into plausible binding modes and to conclude the structure activity relationships of the synthesized compounds. Moreover, anti-inflammatory activity was studied. Compounds 12, 15, 18 and 22 were found to be potent and selective against COX-2.}, type = {Journal Article}, keywords = {Synthesis Quinoxalines Antitumor activity Cyclooxygenase-2 Docking Protein tyrosine kinase} }

[98]

D. Kotowska, R. B. El-Houri, K. Borkowski, R. K. Petersen, X. C. Fretté, G. Wolber, K. Grevsen, K. B. Christensen, L. P. Christensen, and K. Kristiansen. Isomeric C12-Alkamides from the Roots of Echinacea purpurea Improve Basal and Insulin-Dependent Glucose Uptake in 3T3-L1 Adipocytes, Planta Med, 80(18):1712-1720, 2014.
Links: [doi:10.1055/s-0034-1383252] [show BibTeX]  x  @article{RN155, author = {Kotowska, Dorota and El-Houri, Rime B. and Borkowski, Kamil and Petersen, Rasmus K. and Fretté, Xavier C. and Wolber, Gerhard and Grevsen, Kai and Christensen, Kathrine B. and Christensen, Lars P. and Kristiansen, Karsten}, title = {Isomeric C12-Alkamides from the Roots of Echinacea purpurea Improve Basal and Insulin-Dependent Glucose Uptake in 3T3-L1 Adipocytes}, journal = {Planta Med}, volume = {80}, number = {18}, pages = {1712-1720}, ISSN = {0032-0943}, DOI = {10.1055/s-0034-1383252}, url = {https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0034-1383252.pdf}, year = {2014}, type = {Journal Article}, }

[97]

M. S. Murgueitio, P. Henneke, H. Glossmann, S. Santos-Sierra, and G. Wolber. Prospective Virtual Screening in a Sparse Data Scenario: Design of Small-Molecule TLR2 Antagonists, ChemMedChem, 9(4):813-822, 2014.
Links: [doi:10.1002/Cmdc.201300445] [show BibTeX]  x  @article{RN3, author = {Murgueitio, M. S. and Henneke, P. and Glossmann, H. and Santos-Sierra, S. and Wolber, G.}, title = {Prospective Virtual Screening in a Sparse Data Scenario: Design of Small-Molecule TLR2 Antagonists}, journal = {Chemmedchem}, volume = {9}, number = {4}, pages = {813-822}, ISSN = {1860-7179}, DOI = {Doi 10.1002/Cmdc.201300445}, url = {Go to ISI://WOS:000333749200017 http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300445/abstract https://onlinelibrary.wiley.com/doi/pdf/10.1002/cmdc.201300445}, year = {2014}, abtract = {Toll-like receptors (TLRs) are critical signaling molecules with roles in various severe clinical conditions such as sepsis and rheumatoid arthritis, and have therefore been advocated as promising drug targets for the treatment of these diseases. The aim of this study was to discover small-molecule antagonists of TLR2 by computer-aided drug design. This goal poses several challenges due to the lack of available data on TLR2 modulators. To overcome these hurdles we developed a combined structure- and ligand-based virtual screening approach. First, we calculated molecular interaction fields of the TLR2 binding site to derive a structure-based 3D pharmacophore, which was then used for virtual screening. We then performed a two-step shape- and feature-based similarity search using known TLR2 ligands as query structures. A selection of virtual screening hits was biologically tested in a cell-based assay for TLR2 signaling inhibition, leading to the identification of several compounds with antagonistic activity (IC50 values) in the low-micromolar range.}, type = {Journal Article}, keywords = {drug discovery receptors tlr2 antagonists toll-like receptors virtual screening toll-like receptors pattern-recognition receptors pathogen recognition conformer generation structural biology innate immunity binding-sites shape pharmacophores discovery} }

[96]

E. K. Nyakatura, R. R. Araghi, J. Mortier, S. Wieczorek, C. Baldauf, G. Wolber, and B. Koksch. An Unusual Interstrand H-Bond Stabilizes the Heteroassembly of Helical alpha beta gamma-Chimeras with Natural Peptides, ACS Chem Biol, 9(3):613-616, 2014.
Links: [doi:10.1021/Cb4007979] [show BibTeX]  x  @article{RN6, author = {Nyakatura, E. K. and Araghi, R. R. and Mortier, J. and Wieczorek, S. and Baldauf, C. and Wolber, G. and Koksch, B.}, title = {An Unusual Interstrand H-Bond Stabilizes the Heteroassembly of Helical alpha beta gamma-Chimeras with Natural Peptides}, journal = {Acs Chemical Biology}, volume = {9}, number = {3}, pages = {613-616}, ISSN = {1554-8929}, DOI = {Doi 10.1021/Cb4007979}, url = {Go to ISI://WOS:000333477300005 http://pubs.acs.org/doi/pdfplus/10.1021/cb4007979}, year = {2014}, abtract = {The substitution of alpha-amino acids by homologated amino acids has a strong impact on the overall structure and topology of peptides, usually leading to a loss in thermal stability. Here, we report on the identification of an ideal core packing between an alpha-helical peptide and an alpha beta gamma-chimera via phage display. Selected peptides assemble with the chimeric sequence with thermal stabilities that are comparable to that of the parent bundle consisting purely of alpha-amino acids. With the help of MD simulations and mutational analysis this stability could be explained by the formation of an interhelical H-bond between the selected cysteine and a backbone carbonyl of the beta/gamma-segment. Gained results can be directly applied in the design of biologically relevant peptides containing beta- and gamma-amino acids.}, type = {Journal Article}, keywords = {phage display amino-acids foldamers proteins conformations backbone residues insights mimicry design} }

[95]

E. K. Nyakatura, J. Mortier, V. S. Radtke, S. Wieczorek, R. Rezaei Araghi, C. Baldauf, G. Wolber, and B. Koksch. β- and γ-Amino Acids at α-Helical Interfaces: Toward the Formation of Highly Stable Foldameric Coiled Coils, ACS Medicinal Chemistry Letters, 5(12):1300-1303, 2014.
Links: [doi:10.1021/ml500361c] [show BibTeX]  x  @article{RN154, author = {Nyakatura, Elisabeth K. and Mortier, Jérémie and Radtke, Vanessa S. and Wieczorek, Sebastian and Rezaei Araghi, Raheleh and Baldauf, Carsten and Wolber, Gerhard and Koksch, Beate}, title = {β- and γ-Amino Acids at α-Helical Interfaces: Toward the Formation of Highly Stable Foldameric Coiled Coils}, journal = {ACS Medicinal Chemistry Letters}, volume = {5}, number = {12}, pages = {1300-1303}, DOI = {10.1021/ml500361c}, url = {http://dx.doi.org/10.1021/ml500361c http://pubs.acs.org/doi/pdfplus/10.1021/ml500361c}, year = {2014}, abtract = {Since peptides are vital for cellular and pathogenic processes, much effort has been put into the design of unnatural oligomers that mimic natural peptide structures, also referred to as foldamers. However, to enable the specific application of foldamers, a thorough characterization of their interaction profiles in native protein environments is required. We report here the application of phage display for the identification of suitable helical environments for a sequence comprising an alternating set of ?- and ?-amino acids. In vitro selected sequences show that an increase in the hydrophobic surface area at the helical interface as well as the incorporation of a polar H-bond donor functionality can significantly improve interhelical interactions involving backbone-extended amino acids. Thus, our data provide insight into the principles of the rational design of foldameric inhibitors for protein?protein interactions.}, type = {Journal Article}, }

[94]

R. Ottana, R. Maccari, J. Mortier, A. Caselli, S. Amuso, G. Camici, A. Rotondo, G. Wolber, and P. Paoli. Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells, Eur J Med Chem, 71:112-127, 2014.
Links: [doi:10.1016/J.Ejmech.2013.11.001] [show BibTeX]  x  @article{RN9, author = {Ottana, R. and Maccari, R. and Mortier, J. and Caselli, A. and Amuso, S. and Camici, G. and Rotondo, A. and Wolber, G. and Paoli, P.}, title = {Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells}, journal = {European Journal of Medicinal Chemistry}, volume = {71}, pages = {112-127}, ISSN = {0223-5234}, DOI = {Doi 10.1016/J.Ejmech.2013.11.001}, url = {Go to ISI://WOS:000331496100013 http://ac.els-cdn.com/S0223523413007319/1-s2.0-S0223523413007319-main.pdf?_tid= 9b3132fc-4240-11e4-974e-00000aacb361&acdnat=1411380777_e8fb8750bd8d2cbe6a8717d6177ecfcd}, year = {2014}, abtract = {Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we have synthesized new 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3-yl)methyl] benzoic acids (5, 8) and evaluated their inhibitory activity towards human protein tyrosine phosphatases PTP1B, LMW-PTP and TCPTP, enzymes which are involved in the development of insulin resistance. Compounds 5 and 8 showed from moderate to significant selectivity toward PTP1B over both the highly homologous TCPTP and the two isoforms of human LMW-PTP. In addition, most of the tested compounds selectively inhibited LMW-PTP IF1 over the isoform IF2. Docking studies into the active sites of PTP1B and LMW-PTP aided the rationalization of the observed PTP inhibitory profile. Moreover, most tested compounds were capable to induce the insulin metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating both IR beta phosphorylation and 2-deoxyglucose cellular uptake. (C) 2013 Elsevier Masson SAS. All rights reserved.}, type = {Journal Article}, keywords = {protein tyrosine phosphatases enzyme inhibitors insulinomimetic effects molecular docking 5-arylidene-4-thiazolidinone derivatives 4-[(5-arylidene-4-oxo-2-phenylimino/oxothiazolidin-3yl)methyl]benzoic acids weight phosphotyrosyl phosphatase increased insulin sensitivity structure-based optimization cardiovascular-disease signal-transduction alzheimers-disease metabolic syndrome diabetes-mellitus leptin resistance crystal-structure} }

[93]

A. Perdih, M. Hrast, H. Barreteau, S. Gobec, G. Wolber, and T. Solmajer. Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF), Bioorg Med Chem, 22(15):4124-4134, 2014.
Links: [doi:10.1016/j.bmc.2014.05.058] [show BibTeX]  x  @article{RN131, author = {Perdih, Andrej and Hrast, Martina and Barreteau, Hélène and Gobec, Stanislav and Wolber, Gerhard and Solmajer, Tom}, title = {Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF)}, journal = {Bioorganic & Medicinal Chemistry}, volume = {22}, number = {15}, pages = {4124-4134}, ISSN = {0968-0896}, DOI = {10.1016/j.bmc.2014.05.058}, url = {http://www.sciencedirect.com/science/article/pii/S0968089614004179 http://ac.els-cdn.com/S0968089614004179/1-s2.0-S0968089614004179-main.pdf?_tid= 97a047d6-4240-11e4-8cc9-00000aacb35e&acdnat=1411380771_9a11a24bf370dd0c42a4252548df3aaa}, year = {2014}, abtract = {Enzymes catalyzing the biosynthesis of bacterial peptidoglycan represent traditionally a collection of highly selective targets for novel antibacterial drug design. Four members of the bacterial Mur ligase family—MurC, MurD, MurE and MurF—are involved in the intracellular steps of peptidoglycan biosynthesis, catalyzing the synthesis of the peptide moiety of the Park’s nucleotide. In our previous virtual screening campaign, a chemical class of benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives exhibiting dual MurD/MurE inhibition properties was discovered. In the present study we further investigated this class of compounds by performing inhibition assays on all four Mur ligases (MurC–MurF). Furthermore, molecular dynamics (MD) simulation studies of one of the initially discovered compound 1 were performed to explore its geometry as well as its energetic behavior based on the Linear Interaction Energy (LIE) method. Further in silico virtual screening (VS) experiments based on the parent active compound 1 were conducted to optimize the discovered series. Selected hits were assayed against all Escherichia coli MurC–MurF enzymes in biochemical inhibition assays and molecules 10–14 containing benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole coupled with five member-ring rhodanine moiety were found to be multiple inhibitors of the whole MurC–MurF cascade of bacterial enzymes in the micromolar range. Steady-state kinetics studies suggested this class to act as competitive inhibitors of the MurD enzyme towards d-Glu. These compounds represent novel valuable starting point in the development of novel antibacterial agents.}, type = {Journal Article}, keywords = {Bacterial Mur (MurC–MurF) ligase Structure-based pharmacophores Virtual screening Molecular docking Molecular dynamics (MD) Linear Interaction Energy (LIE) method Antibacterial agents Drug design} }

[92]

A. Perdih, M. Hrast, H. Barreteau, S. Gobec, G. Wolber, and T. Solmajer. Inhibitor Design Strategy Based on an Enzyme Structural Flexibility: A Case of Bacterial MurD Ligase, J Chem Inf Model, 54(5):1451-1466, 2014.
Links: [doi:10.1021/Ci500104m] [show BibTeX]  x  @article{RN2, author = {Perdih, A. and Hrast, M. and Barreteau, H. and Gobec, S. and Wolber, G. and Solmajer, T.}, title = {Inhibitor Design Strategy Based on an Enzyme Structural Flexibility: A Case of Bacterial MurD Ligase}, journal = {Journal of Chemical Information and Modeling}, volume = {54}, number = {5}, pages = {1451-1466}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci500104m}, url = {Go to ISI://WOS:000336637400016 http://pubs.acs.org/doi/pdfplus/10.1021/ci500104m}, year = {2014}, abtract = {Increasing bacterial resistance to available antibiotics stimulated the discovery of novel efficacious antibacterial agents. The biosynthesis of the bacterial peptidoglycan, where the MurD enzyme is involved in the intracellular phase of the UDP-MurNAc-pentapeptide formation, represents a collection of highly selective targets for novel antibacterial drug design. In our previous computational studies, the C-terminal domain motion of the MurD ligase was investigated using Targeted Molecular Dynamic (TMD) simulation and the Off-Path Simulation (OPS) technique. In this study, we present a drug design strategy using multiple protein structures for the identification of novel MurD ligase inhibitors. Our main focus was the ATP-binding site of the MurD enzyme. In the first stage, three MurD protein conformations were selected based on the obtained OPS/TMD data as the initial criterion. Subsequently, a two-stage virtual screening approach was utilized combining derived structure-based pharmacophores with molecular docking calculations. Selected compounds were then assayed in the established enzyme binding assays, and compound 3 from the aminothiazole class was discovered to act as a dual MurC/MurD inhibitor in the micomolar range. A steady-state kinetic study was performed on the MurD enzyme to provide further information about the mechanistic aspects of its inhibition. In the final stage, all used conformations of the MurD enzyme with compound 3 were simulated in classical molecular dynamics (MD) simulations providing atomistic insights of the experimental results. Overall, the study depicts several challenges that need to be addressed when trying to hit a flexible moving target such as the presently studied bacterial MurD enzyme and show the possibilities of how computational tools can be proficiently used at all stages of the drug discovery process.}, type = {Journal Article}, keywords = {molecular-dynamics simulation escherichia-coli peptidoglycan biosynthesis protein flexibility drug discovery kinetic mechanism hiv-1 protease adding enzyme force-fields cell-wall} }

[91]

C. Rakers, S. Schwerdtfeger, J. Mortier, S. Duwe, T. Wolff, G. Wolber, and M. F. Melzig. Inhibitory potency of flavonoid derivatives on influenza virus neuraminidase, Bioorg Med Chem Lett, 24(17):4312-4317, 2014.
Links: [doi:10.1016/j.bmcl.2014.07.010] [show BibTeX]  x  @article{RN130, author = {Rakers, Christin and Schwerdtfeger, Sverre-Morten and Mortier, Jérémie and Duwe, Susanne and Wolff, Thorsten and Wolber, Gerhard and Melzig, Matthias F.}, title = {Inhibitory potency of flavonoid derivatives on influenza virus neuraminidase}, journal = {Bioorganic & Medicinal Chemistry Letters}, volume = {24}, number = {17}, pages = {4312-4317}, ISSN = {0960-894X}, DOI = {10.1016/j.bmcl.2014.07.010}, url = {http://www.sciencedirect.com/science/article/pii/S0960894X14007343 http://ac.els-cdn.com/S0960894X14007343/1-s2.0-S0960894X14007343-main.pdf?_tid= 9244019c-4240-11e4-af5e-00000aab0f27&acdnat=1411380762_b399fa4d56fe704fa20d99c706fd5f57}, year = {2014}, abtract = {The constant risk of emerging new influenza virus strains that are resistant to established inhibitors like oseltamivir leaves influenza neuraminidase (NA) a prominent target for drug design. The inhibitory activity of several flavonoid derivatives was experimentally tested in comparison to oseltamivir for the NA expressed by the seasonal influenza virus strains A/California/7/09 (A(H1N1)pdm09), A/Perth/16/09 (A(H3N2)), and B/Brisbane/60/08. IC50 values of polyphenols confirmed moderate inhibition in the μM range. Structurally, the amount and site of glycosylation of tested flavonoids have no significant influence on their inhibitory potency. In a pharmacophore-based docking approach the structure–activity relationship was evaluated. Molecular dynamics simulations revealed highly flexible parts of the enzyme and the contribution of salt bridges to the structural stability of NA. The findings of this study elucidate the impact of flavonoids on viral neuraminidase activity and the analysis of their modes of action provide valuable information about the mechanism of NA inhibition.}, type = {Journal Article}, keywords = {Influenza Neuraminidase Flavonoids Molecular dynamics Docking} }

[90]

J. Schmitz, D. van der Mey, M. Bermudez, J. Klöckner, R. Schrage, E. Kostenis, C. Tränkle, G. Wolber, K. Mohr, and U. Holzgrabe. Dualsteric Muscarinic Antagonists - Orthosteric Binding Pose Controls Allosteric Subtype Selectivity, J Med Chem, 57(15):6739-6750, 2014.
Links: [doi:10.1021/jm500790x] [show BibTeX]  x  @article{RN129, author = {Schmitz, Jens and van der Mey, Dorina and Bermudez, Marcel and Klöckner, Jessica and Schrage, Ramona and Kostenis, Evi and Tränkle, Christian and Wolber, Gerhard and Mohr, Klaus and Holzgrabe, Ulrike}, title = {Dualsteric Muscarinic Antagonists - Orthosteric Binding Pose Controls Allosteric Subtype Selectivity}, journal = {Journal of Medicinal Chemistry}, volume = {57}, number = {15}, pages = {6739-6750}, ISSN = {0022-2623}, DOI = {10.1021/jm500790x}, url = {http://pubs.acs.org/doi/pdfplus/10.1021/jm500790x}, year = {2014}, abtract = {Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal- and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure–activity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.}, type = {Journal Article}, keywords = {gpcr} }

[89]

M. A. Seiter, S. Salcher, M. Rupp, J. Hagenbuchner, U. Kiechl-Kohlendorfer, J. Mortier, G. Wolber, J. M. Rollinger, P. Obexer, and M. J. Ausserlechner. Discovery of Sanggenon G as a natural cell-permeable small-molecular weight inhibitor of X-linked inhibitor of apoptosis protein (XIAP), FEBS Open Bio, 4:659-671, 2014.
Links: [doi:10.1016/j.fob.2014.07.001] [show BibTeX]  x  @article{RN132, author = {Seiter, Maximilian A. and Salcher, Stefan and Rupp, Martina and Hagenbuchner, Judith and Kiechl-Kohlendorfer, Ursula and Mortier, Jérémie and Wolber, Gerhard and Rollinger, Judith M. and Obexer, Petra and Ausserlechner, Michael J.}, title = {Discovery of Sanggenon G as a natural cell-permeable small-molecular weight inhibitor of X-linked inhibitor of apoptosis protein (XIAP)}, journal = {FEBS Open Bio}, volume = {4}, number = {0}, pages = {659-671}, ISSN = {2211-5463}, DOI = {10.1016/j.fob.2014.07.001}, url = {http://www.sciencedirect.com/science/article/pii/S2211546314000655 http://ac.els-cdn.com/S2211546314000655/1-s2.0-S2211546314000655-main.pdf?_tid= 8f475c96-4240-11e4-ad09-00000aacb360&acdnat=1411380757_e7c5cf33054a97e0fc81b36bee35993e}, year = {2014}, abtract = {Defects in the regulation of apoptosis are one main cause of cancer development and may result from overexpression of anti-apoptotic proteins such as the X-linked inhibitor of apoptosis protein (XIAP). XIAP is frequently overexpressed in human leukemia and prostate and breast tumors. Inhibition of apoptosis by XIAP is mainly coordinated through direct binding to the initiator caspase-9 via its baculovirus-IAP-repeat-3 (BIR3) domain. XIAP inhibits caspases directly making it to an attractive target for anti-cancer therapy. In the search for novel, non-peptidic XIAP inhibitors in this study we focused on the chemical constituents of sāng bái pí (mulberry root bark). Most promising candidates of this plant were tested biochemically in vitro by a fluorescence polarization (FP) assay and in vivo via protein fragment complementation analysis (PCA). We identified the Diels Alder adduct Sanggenon G (SG1) as a novel, small-molecular weight inhibitor of XIAP. As shown by FP and PCA analyses, SG1 binds specifically to the BIR3 domain of XIAP with a binding affinity of 34.26 μM. Treatment of the transgenic leukemia cell line Molt3/XIAP with SG1 enhances caspase-8, -3 and -9 cleavage, displaces caspase-9 from XIAP as determined by immunoprecipitation experiments and sensitizes these cells to etoposide-induced apoptosis. SG1 not only sensitizes the XIAP-overexpressing leukemia cell line Molt3/XIAP to etoposide treatment but also different neuroblastoma cell lines endogenously expressing high XIAP levels. Taken together, Sanggenon G (SG1) is a novel, natural, non-peptidic, small-molecular inhibitor of XIAP that can serve as a starting point to develop a new class of improved XIAP inhibitors.}, type = {Journal Article}, keywords = {application sbdd} }

[88]

A. Temirak, Y. M. Shaker, F. A. F. Ragab, M. M. Ali, S. M. Soliman, J. Mortier, G. Wolber, H. I. Ali, and H. I. El Diwani. Synthesis, Biological Evaluation, and Docking Studies of New 2-Furylbenzimidazoles as Anti- Angiogenic Agents: Part II, Arch Pharm, 347(4):291-304, 2014.
Links: [doi:10.1002/Ardp.201300356] [show BibTeX]  x  @article{RN4, author = {Temirak, A. and Shaker, Y. M. and Ragab, F. A. F. and Ali, M. M. and Soliman, S. M. and Mortier, J. and Wolber, G. and Ali, H. I. and El Diwani, H. I.}, title = {Synthesis, Biological Evaluation, and Docking Studies of New 2-Furylbenzimidazoles as Anti- Angiogenic Agents: Part II}, journal = {Archiv Der Pharmazie}, volume = {347}, number = {4}, pages = {291-304}, ISSN = {0365-6233}, DOI = {Doi 10.1002/Ardp.201300356}, url = {Go to ISI://WOS:000333686700008 http://onlinelibrary.wiley.com/store/10.1002/ardp.201300356/asset/ardp201300356.pdf?v= 1&t=i0dnk0o7&s=adf05599c316cb9a97e07a9131eb4f64f613102a}, year = {2014}, abtract = {The 2-(5-methyl-2-furyl)-1H-benzimidazole moiety has shown promising activity against vascular endothelial growth factor (VEGF)-induced angiogenesis. In part I of this study, we have synthesized new analogs and tested their anti-angiogenic potentials. Here, we continue our previous study with different new analogs. Some compounds show promising cytotoxic activity against the human breast cancer cell line MCF-7, with IC50 in the range of 7.80-13.90 mu g/mL, and exhibited remarkable in vitro inhibition against VEGF in the MCF-7 cancer cell line, with 95-98% of inhibition in comparison to tamoxifen as reference (IC50: 8.00 mu g/mL, % of inhibition=98%). Additionally, a molecular docking study was carried out to gain insight into plausible binding modes and to understand the structure-activity relationships of the synthesized compounds.}, type = {Journal Article}, keywords = {application} }

[87]

C. D. Cadicamo, J. Mortier, G. Wolber, M. Hell, I. E. Heinrich, D. Michel, L. Semlin, U. Berger, H. C. Korting, H. D. Holtje, B. Koksch, and C. Borelli. Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans, Biochem Pharmacol, 85(7):881-887, 2013.
Links: [doi:10.1016/J.Bcp.2012.12.008] [show BibTeX]  x  @article{RN19, author = {Cadicamo, C. D. and Mortier, J. and Wolber, G. and Hell, M. and Heinrich, I. E. and Michel, D. and Semlin, L. and Berger, U. and Korting, H. C. and Holtje, H. D. and Koksch, B. and Borelli, C.}, title = {Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans}, journal = {Biochemical Pharmacology}, volume = {85}, number = {7}, pages = {881-887}, ISSN = {0006-2952}, DOI = {Doi 10.1016/J.Bcp.2012.12.008}, url = {Go to ISI://WOS:000316423000004 http://ac.els-cdn.com/S0006295212007940/1-s2.0-S0006295212007940-main.pdf?_tid= b5706d5e-4240-11e4-87eb-00000aab0f27&acdnat=1411380821_0911f281fa7759a5300962e9ca09acb7}, year = {2013}, abtract = {The family of secreted aspartic proteinases is known as an important virulence factor of yeast infections by Candida albicans in particular, which is the most common fungal pathogen for humans with respect to systemic disease. Due to the continuing increase of drug resistant strains, these proteinases are currently considered as promising drug target candidates. Based on the known Sap2-substrate specificity data and X-ray analyses of Sap/inhibitor complexes, three libraries of inhibitors were designed and synthesized by modifying the structure of pepstatin A, a common non-selective aspartic proteinase inhibitor, at the P3, P2, or P2' position. These novel inhibitors showed high inhibitory potencies for the isoenzymes Sap1, Sap3, Sap5 and Sap6. Then, the affinity and selectivity of the peptide ligands were investigated by molecular modeling, highlighting new key structural information for the design of potent and selective anti-virulence agents targeting Candida albicans. (c) 2012 Elsevier Inc. All rights reserved.}, type = {Journal Article}, keywords = {anti-virulence agent peptidomimetic candidapeptidase secreted aspartic proteinases inhibition pepstatin candida albicans solid-phase synthesis crystal-structure in-vivo virulence expression proteases pharmacophores parapsilosis pathogenesis repository} }

[86]

K. N. de Oliveira, V. Andermark, S. von Grafenstein, L. A. Onambele, G. Dahl, R. Rubbiani, G. Wolber, C. Gabbiani, L. Messori, A. Prokop, and I. Ott. Butyltin(IV) Benzoates: Inhibition of Thioredoxin Reductase, Tumor Cell Growth Inhibition, and Interactions with Proteins, ChemMedChem, 8(2):256-264, 2013.
Links: [doi:10.1002/Cmdc.201200505] [show BibTeX]  x  @article{RN20, author = {de Oliveira, K. N. and Andermark, V. and von Grafenstein, S. and Onambele, L. A. and Dahl, G. and Rubbiani, R. and Wolber, G. and Gabbiani, C. and Messori, L. and Prokop, A. and Ott, I.}, title = {Butyltin(IV) Benzoates: Inhibition of Thioredoxin Reductase, Tumor Cell Growth Inhibition, and Interactions with Proteins}, journal = {Chemmedchem}, volume = {8}, number = {2}, pages = {256-264}, ISSN = {1860-7179}, DOI = {Doi 10.1002/Cmdc.201200505}, url = {Go to ISI://WOS:000314172700008 http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200505/abstract http://onlinelibrary.wiley.com/store/10.1002/cmdc.201200505/asset/256_ftp.pdf?v= 1&t=jdvll0lr&s=8cf79c478b87e51f4c1b5bb9748efa83ed85b36a}, year = {2013}, abtract = {Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di- and tri-n-butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT-29 and MCF-7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di-n-butyltin(IV) complex as an example.}, type = {Journal Article}, keywords = {virtual screening antitumor agents bioorganometallics thioredoxin reductases tin gold(i) complexes cancer-therapy organometallic compounds carboxylate complexes organotin compounds antitumor-activity metal-complexes tin compound agents} }

[85]

M. Enthammer, E. S. Papadakis, M. S. Gachet, M. Deutsch, S. Schwaiger, K. Koziel, M. I. Ashraf, S. Khalid, G. Wolber, G. Packham, R. I. Cutress, H. Stuppner, and J. Troppmair. Isolation of a Novel Thioflavin S-Derived Compound That Inhibits BAG-1-Mediated Protein Interactions and Targets BRAF Inhibitor-Resistant Cell Lines, Mol Cancer Ther, 12(11):2400-2414, 2013.
Links: [doi:10.1158/1535-7163.Mct-13-0142] [show BibTeX]  x  @article{RN12, author = {Enthammer, M. and Papadakis, E. S. and Gachet, M. S. and Deutsch, M. and Schwaiger, S. and Koziel, K. and Ashraf, M. I. and Khalid, S. and Wolber, G. and Packham, G. and Cutress, R. I. and Stuppner, H. and Troppmair, J.}, title = {Isolation of a Novel Thioflavin S-Derived Compound That Inhibits BAG-1-Mediated Protein Interactions and Targets BRAF Inhibitor-Resistant Cell Lines}, journal = {Molecular Cancer Therapeutics}, volume = {12}, number = {11}, pages = {2400-2414}, ISSN = {1535-7163}, DOI = {Doi 10.1158/1535-7163.Mct-13-0142}, url = {Go to ISI://WOS:000326886000011 http://mct.aacrjournals.org/content/12/11/2400 http://mct.aacrjournals.org/content/12/11/2400.full.pdf}, year = {2013}, abtract = {Protein-protein interactions mediated through the C-terminal Bcl-2-associated athanogene (BAG) domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948)-a mixture of compounds resulting from the methylation and sulfonation of primulin base-has been shown to dose-dependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70, or CRAF and decreases proliferation and viability. Here, we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines, but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells, Thio-2 interfered with intracellular signaling at the level of RAF, but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies. (C) 2013 AACR.}, type = {Journal Article}, keywords = {b-raf acquired-resistance thiazole dyes human cancer melanoma kinase mutations survival bag-1 activation} }

[84]

S. A. Galar, A. S. Abdelsamie, S. M. Soliman, J. Mortier, G. Wolber, M. M. Ali, H. Tokuda, N. Suzuki, A. Lida, R. A. Ramadan, and H. I. El Diwani. Design, synthesis and structure-activity relationship of novel quinoxaline derivatives as cancer chemopreventive agent by inhibition of tyrosine kinase receptor, Eur J Med Chem, 69:115-124, 2013.
Links: [doi:10.1016/J.Ejmech.2013.07.049] [show BibTeX]  x  @article{RN13, author = {Galar, S. A. and Abdelsamie, A. S. and Soliman, S. M. and Mortier, J. and Wolber, G. and Ali, M. M. and Tokuda, H. and Suzuki, N. and Lida, A. and Ramadan, R. A. and El Diwani, H. I.}, title = {Design, synthesis and structure-activity relationship of novel quinoxaline derivatives as cancer chemopreventive agent by inhibition of tyrosine kinase receptor}, journal = {European Journal of Medicinal Chemistry}, volume = {69}, pages = {115-124}, ISSN = {0223-5234}, DOI = {Doi 10.1016/J.Ejmech.2013.07.049}, url = {Go to ISI://WOS:000330603900011 http://ac.els-cdn.com/S0223523413005023/1-s2.0-S0223523413005023-main.pdf?_tid= ab4af826-4240-11e4-a1d8-00000aacb35d&acdnat=1411380804_70af19db3712904ba5a3c4ccdd1783ee}, year = {2013}, abtract = {The cancer chemopreventive activity of quinoxaline derivatives 1-20 has been evaluated by studying the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation. The quinoxaline derivatives 1-20 showed inhibitory effect on EBV-EA activation without cytotoxicity on Raji cells. All compounds exhibited dose dependent inhibitory activities, most of them showed significant activity at 1000 mol ratio/12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 7 and 9 exhibited stronger inhibitory effects on the EBV-EA activation than that of the representative control, oleanolic acid, at the highest measured concentration. In addition, compounds 7-10 showed potent and selective inhibition of human tyrosine kinase (TRK) in liver cancer HepG2 and breast cancer MCF-7 cell lines similar to the positive control, doxorubicin. (C) 2013 Published by Elsevier Masson SAS.}, type = {Journal Article}, keywords = {synthesis quinoxalines epstein-barr virus cancer chemopreventive activity docking protein tyrosine kinase antitumor-activity protein-kinases ethyl carboethoxyformimidate cells phosphorylation hydrazine melanoma drug} }

[83]

J. Leschner, G. Wennerberg, J. Feierler, M. Bermudez, B. Welte, I. Kalatskaya, G. Wolber, and A. Faussner. Interruption of the Ionic Lock in the Bradykinin B-2 Receptor Results in Constitutive Internalization and Turns Several Antagonists into Strong Agonists, J Pharmacol Exp Ther, 344(1):85-95, 2013.
Links: [doi:10.1124/Jpet.112.199190] [show BibTeX]  x  @article{RN21, author = {Leschner, J. and Wennerberg, G. and Feierler, J. and Bermudez, M. and Welte, B. and Kalatskaya, I. and Wolber, G. and Faussner, A.}, title = {Interruption of the Ionic Lock in the Bradykinin B-2 Receptor Results in Constitutive Internalization and Turns Several Antagonists into Strong Agonists}, journal = {Journal of Pharmacology and Experimental Therapeutics}, volume = {344}, number = {1}, pages = {85-95}, ISSN = {0022-3565}, DOI = {Doi 10.1124/Jpet.112.199190}, url = {Go to ISI://WOS:000312805500011 http://jpet.aspetjournals.org/content/344/1/85.full.pdf}, year = {2013}, abtract = {The DRY motif with the highly conserved R3.50 is a hallmark of family A G protein-coupled receptors (GPCRs). The crystal structure of rhodopsin revealed a salt bridge between R135(3.50) and another conserved residue, E247(6.30), in helix 6. This ionic lock was shown to maintain rhodopsin in its inactive state. Thus far, little information is available on how interruption of this ionic bond affects signaling properties of nonrhodopsin GPCRs, because the focus has been on mutations of R3.50, although this residue is indispensable for G protein activation. To investigate the importance of an ionic lock for overall receptor activity in a nonrhodopsin GPCR, we mutated R128(3.50) and E238(6.30) in the bradykinin (BK) B-2 receptor (B2R) and stably expressed the constructs in HEK293 cells. As expected, mutation of R3.50 resulted in lack of G protein activation. In addition, this mutation led to considerable constitutive receptor internalization. Mutation of E6.30 (mutants E6.30A and E6.30R) also caused strong constitutive internalization. Most intriguingly, however, although the two E6.30 mutants displayed no increased basal phosphatidylinositol hydrolysis, they gave a response to three different B2R antagonists that was almost comparable to that obtained with BK. In contrast, swapping of R3.50 and E6.30, thus allowing the formation of an inverse ionic bond, resulted in rescue of the wild type phenotype. These findings demonstrate for the first time, to our knowledge, that interruption of the ionic lock in a family A GPCR can have distinctly different effects on receptor internalization and G protein stimulation, shedding new light on its role in the activation process.}, type = {Journal Article}, keywords = {protein-coupled receptors beta(2)-adrenergic receptor phosphorylation sites crystal-structure beta-arrestin ground-state dry motif activation rhodopsin model gpcr} }

[82]

M. Levay, K. A. Krobert, K. Wittig, N. Voigt, M. Bermudez, G. Wolber, D. Dobrev, F. O. Levy, and T. Wieland. NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors, J Pharmacol Exp Ther, 347(1):69-79, 2013.
Links: [doi:10.1124/Jpet.113.207266] [show BibTeX]  x  @article{RN14, author = {Levay, M. and Krobert, K. A. and Wittig, K. and Voigt, N. and Bermudez, M. and Wolber, G. and Dobrev, D. and Levy, F. O. and Wieland, T.}, title = {NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors}, journal = {Journal of Pharmacology and Experimental Therapeutics}, volume = {347}, number = {1}, pages = {69-79}, ISSN = {0022-3565}, DOI = {Doi 10.1124/Jpet.113.207266}, url = {Go to ISI://WOS:000324583600008 http://jpet.aspetjournals.org/content/347/1/69.full.pdf}, year = {2013}, abtract = {Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(N-6-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride]. We found that NSC23766 inhibits the M-2 muscarinic acetylcholine receptor (M-2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M-2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rho-dependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M-2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly G(i)beta gamma-mediated, adenosine-induced activation of G(i) protein-regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K+ current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A(1) receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca2+ concentrations in human embryonic kidney 293 (HEK-293) cells expressing M-1, M-2, or M-3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M-2 and M-3 mAChR crystal structures confirmed this interpretation.}, type = {Journal Article}, keywords = {spine remodeling contributes chronic atrial-fibrillation small-molecule inhibitor heart-failure rho-gtpases i-k,i-ach channels rat cardiomyocytes neuropathic pain g-proteins injury gpcr} }

[81]

A. Perdih, G. Wolber, and T. Solmajer. Molecular dynamics simulation and linear interaction energy study of d-Glu-based inhibitors of the MurD ligase, J Comput Aided Mol Des, 27(8):723-738, 2013.
Links: [doi:10.1007/S10822-013-9673-3] [show BibTeX]  x  @article{RN15, author = {Perdih, A. and Wolber, G. and Solmajer, T.}, title = {Molecular dynamics simulation and linear interaction energy study of d-Glu-based inhibitors of the MurD ligase}, journal = {Journal of Computer-Aided Molecular Design}, volume = {27}, number = {8}, pages = {723-738}, ISSN = {0920-654X}, DOI = {Doi 10.1007/S10822-013-9673-3}, url = {Go to ISI://WOS:000324334600008 http://download.springer.com/static/pdf/612/art%253A10.1007%252Fs10822-013-9673-3.pdf?auth66= 1411553415_824cfb4729b999d5c774dd2180f661a4&ext=.pdf}, year = {2013}, abtract = {The biosynthetic pathway of the bacterial peptidoglycan, where MurD is an enzyme involved at the intracellular stage of its construction, represents a collection of highly selective macromolecular targets for novel antibacterial drug design. In this study as part of our investigation of the MurD bacterial target two recently discovered classes of the MurD ligase inhibitors were investigated resulting from the lead optimization phases of the N-sulfonamide d-Glu MurD inhibitors. Molecular dynamics simulations, based on novel structural data, in conjunction with the linear interaction energy (LIE) method suggested the transferability of our previously obtained LIE coefficients to further d-Glu based classes of MurD inhibitors. Analysis of the observed dynamical behavior of these compounds in the MurD active site was supported by static drug design techniques. These results complement the current knowledge of the MurD inhibitory mechanism and provide valuable support for the d-Glu paradigm of the inhibitor design.}, type = {Journal Article}, keywords = {molecular dynamics (md) simulations linear interaction energy (lie) method structure-based pharmacophore models murd ligase antibacterial agents drug design d-glutamic acid adding enzyme kinase inhibitors organic-molecules kinetic mechanism binding-affinity drug design discovery pharmacophores derivatives} }

[80]

M. Spetea, M. F. Asim, S. Noha, G. Wolber, and H. Schmidhammer. Current kappa Opioid Receptor Ligands and Discovery of a New Molecular Scaffold as a kappa Opioid Receptor Antagonist Using Pharmacophore-Based Virtual Screening, Curr Pharm Design, 19(42):7362-7372, 2013.
Links: [show BibTeX]  x  @article{RN10, author = {Spetea, M. and Asim, M. F. and Noha, S. and Wolber, G. and Schmidhammer, H.}, title = {Current kappa Opioid Receptor Ligands and Discovery of a New Molecular Scaffold as a kappa Opioid Receptor Antagonist Using Pharmacophore-Based Virtual Screening}, journal = {Current Pharmaceutical Design}, volume = {19}, number = {42}, pages = {7362-7372}, ISSN = {1381-6128}, url = {Go to ISI://WOS:000329431900005 http://www.eurekaselect.com/111859/article}, year = {2013}, abtract = {The kappa opioid receptor (KOR) plays a significant role in many physiological functions, including pain relief, stress, depression, drug abuse, anxiety and psychotic behaviors. KORs are widely distributed in the central and peripheral nervous systems, and are specifically activated by endogenous opioids derived from prodynorphin. They are members of the G protein-coupled receptor superfamily, and the crystal structure of the human KOR was recently elucidated. KORs were initially studied for their involvement in mediation of pain as stimulation of KOR produces analgesia and minimizes abuse liability and other side effects. Nowadays, the KOR is rapidly emerging as an important target for the treatment of a variety of other human disorders. Specifically, the KOR system has become increasingly implicated as a modulator of stress-related and addictive behaviors. Several selective KOR partial agonists and antagonists have been developed as potential antidepressants, anxiolytic and anti-addiction medications. Although many KOR ligands have not demonstrated desirable pharmacological properties, some have been shown to be viable drug candidates. Herein, we describe chemical and pharmacological developments on KOR ligands, advantages and challenges, and potential therapeutic applications of ligands for KORs. In the second part, recent advances in the KOR drug design utilizing computational approaches are presented, with focus on the discovery of a new naturally derived scaffold, sewarine, as a novel class of selective KOR ligands with antagonist properties, using a pharmacophore-based virtual screening strategy.}, type = {Journal Article}, keywords = {kappa opioid receptor agonist antagonist sewarine drug design pharmacophore virtual screening protein coupled receptors in-silico pharmacology rhazya-stricta drug discovery adjuvant arthritis natural-products analgesic efficacy highly potent agonist identification} }

[79]

M. Spetea, M. F. Asim, G. Wolber, and H. Schmidhammer. The mu Opioid Receptor and Ligands Acting at the mu Opioid Receptor, as Therapeutics and Potential Therapeutics, Curr Pharm Design, 19(42):7415-7434, 2013.
Links: [show BibTeX]  x  @article{RN11, author = {Spetea, M. and Asim, M. F. and Wolber, G. and Schmidhammer, H.}, title = {The mu Opioid Receptor and Ligands Acting at the mu Opioid Receptor, as Therapeutics and Potential Therapeutics}, journal = {Current Pharmaceutical Design}, volume = {19}, number = {42}, pages = {7415-7434}, ISSN = {1381-6128}, url = {Go to ISI://WOS:000329431900010 http://www.eurekaselect.com/108136/article}, year = {2013}, abtract = {Although the mu opioid receptor (MOR) was pharmacologically and biochemically identified in binding studies forty years ago, its structure, function, and true complexity only have emerged after its cloning in 1993. Continuous efforts from many laboratories have greatly advanced our understanding of MORs, ranging from their anatomic distribution to cellular and molecular mechanisms, and from cell lines to in vivo systems. The MOR is recognized as the main target for effective pain relief, but its involvement in many other physiological functions has also been recognized. This review provides a synopsis on the history of research on MORs and ligands acting at the MOR with the focus on their clinical and potential use as therapeutic drugs, or as valuable research tools. Since the elucidation of the chemical structure of morphine and the characterization of endogenous opioid peptides, research has stimulated the development of new generations of MOR ligands with distinct pharmacological profiles (agonist, antagonist, mixed agonist/antagonist and partial agonist) or site of action (central/peripheral). Discovery of therapeutically useful morphine-like drugs and innovative drugs with new scaffolds, with several outstanding representatives, is discussed. Extensive efforts on modifications of endogenous peptides to attain stable and MOR selective analogs are overviewed with stimulating results for the development of peptide-based pharmaceuticals. With pharmacophore modeling as an important tool in drug discovery, application of modern computational methodologies for the development of morphinans as new MOR ligands is described. Moreover, the crystal structure of the MOR available today will enable the application of structure-based approaches to design better drugs for the management of pain, addiction and other human diseases, where MORs play a key role.}, type = {Journal Article}, keywords = {mu opioid receptor pain agonist antagonist morphine morphinans pharmacophore acid-substituted derivatives selective agonist binding protein-coupled receptors 3rd extracellular loop pharmacological characterization biological evaluation opiate receptor in-vitro drug discovery highly potent} }

[78]

S. Distinto, F. Esposito, J. Kirchmair, M. C. Cardia, M. Gaspari, E. Maccioni, S. Alcaro, P. Markt, G. Wolber, L. Zinzula, and E. Tramontano. Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach, Eur J Med Chem, 50:216-229, 2012.
Links: [doi:10.1016/J.Ejmech.2012.01.056] [show BibTeX]  x  @article{RN31, author = {Distinto, S. and Esposito, F. and Kirchmair, J. and Cardia, M. C. and Gaspari, M. and Maccioni, E. and Alcaro, S. and Markt, P. and Wolber, G. and Zinzula, L. and Tramontano, E.}, title = {Identification of HIV-1 reverse transcriptase dual inhibitors by a combined shape-, 2D-fingerprint- and pharmacophore-based virtual screening approach}, journal = {European Journal of Medicinal Chemistry}, volume = {50}, pages = {216-229}, ISSN = {0223-5234}, DOI = {Doi 10.1016/J.Ejmech.2012.01.056}, url = {Go to ISI://WOS:000303284400024 http://ac.els-cdn.com/S0223523412000724/1-s2.0-S0223523412000724-main.pdf?_tid= d2a118ce-4240-11e4-a14f-00000aab0f02&acdnat=1411380870_38ae86ece5f644d61da0c34a1b013bb3}, year = {2012}, abtract = {We report the first application of ligand-based virtual screening (VS) methods for discovering new compounds able to inhibit both human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT)-associated functions, DNA polymerase and ribonuclease H (RNase H) activities. The overall VS campaign consisted of two consecutive screening processes. In the first, the VS platform Rapid Overlay of Chemical Structures (ROCS) was used to perform in silico shape-based similarity screening on the NCI compounds database in which a hydrazone derivative, previously shown to inhibit the HIV-1 RI, was chosen. As a result, 34 hit molecules were selected and assayed on both RI-associated functions. In the second, the 4 most potent RI inhibitors identified were selected as queries for parallel VS performed by combining shape-based, 2D-fingerprint and 3D-pharmacophore VS methods. Overall, a set of molecules characterized by new different scaffolds were identified as novel inhibitors of both HIV-1 RI-associated activities in the low micromolar range. (C) 2012 Elsevier Masson SAS. All rights reserved.}, type = {Journal Article}, keywords = {hiv molecular fingerprints pharmacophore rnase h shape virtual screening rnase-h activity ribonuclease-h molecular docking accurate docking recent progress binding-sites active-site replication discovery database} }

[77]

S. Distinto, M. Yanez, S. Alcaro, M. C. Cardia, M. Gaspari, M. L. Sanna, R. Meleddu, F. Ortuso, J. Kirchmair, P. Markt, A. Bolasco, G. Wolber, D. Secci, and E. Maccioni. Synthesis and biological assessment of novel 2-thiazolylhydrazones and computational analysis of their recognition by monoamine oxidase B, Eur J Med Chem, 48:284-295, 2012.
Links: [doi:10.1016/J.Ejmech.2011.12.027] [show BibTeX]  x  @article{RN35, author = {Distinto, S. and Yanez, M. and Alcaro, S. and Cardia, M. C. and Gaspari, M. and Sanna, M. L. and Meleddu, R. and Ortuso, F. and Kirchmair, J. and Markt, P. and Bolasco, A. and Wolber, G. and Secci, D. and Maccioni, E.}, title = {Synthesis and biological assessment of novel 2-thiazolylhydrazones and computational analysis of their recognition by monoamine oxidase B}, journal = {European Journal of Medicinal Chemistry}, volume = {48}, pages = {284-295}, ISSN = {0223-5234}, DOI = {Doi 10.1016/J.Ejmech.2011.12.027}, url = {Go to ISI://WOS:000300484900029 http://ac.els-cdn.com/S0223523411009081/1-s2.0-S0223523411009081-main.pdf?_tid= cfaf5680-4240-11e4-a5cd-00000aacb361&acdnat=1411380865_c4b345c249fcef3e4fe2ac8146c7d68f}, year = {2012}, abtract = {Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines. The fluorinated series shows interesting activity and great selectivity toward the human recombinant MAO-B isoform expressed in baculovirus infected BTI insect cells. The multiple crystal structures alignment of the enzyme highlighted pronounced induced fit (IF) adaptations with respect to bound ligands. Therefore, IF docking (IFD) experiments and molecular dynamic (MD) simulations were carried out to reveal the putative binding mode and to explain the experimentally observed differences in the activity of 1-(aryliden-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazines. The importance of water molecules within the binding site was also investigated. These are known to play an important role in the binding site cavity and to mediate protein ligand interactions. Detailed analyses of the trajectories provide insights on the chemical features required for the activity of this scaffold. In particular it was highlighted the importance of fluorine atom interacting with the water close to the cofactor and the influence of steric bulkiness of substituents in the arylidene moiety. Free energy perturbation (FEP) analysis confirmed experimental data. The information we deduced will help to develop novel high-affinity MAO-B inhibitors. (C) 2011 Elsevier Masson SAS. All rights reserved.}, type = {Journal Article}, keywords = {fep grid induced fit docking mao-b inhibitors molecular dynamics selective inhibitory-activity molecular-dynamics parkinsons-disease drug discovery structural insights medicinal chemistry crystal-structures binding-sites docking mao} }

[76]

A. Faussner, S. Schussler, J. Feierler, M. Bermudez, J. Pfeifer, K. Schnatbaum, T. Tradler, M. Jochum, G. Wolber, and C. Gibson. Binding characteristics of [3H]-JSM10292: a new cell membrane-permeant non-peptide bradykinin B2 receptor antagonist, Br J Pharmacol, 167(4):839-853, 2012.
Links: [doi:10.1111/J.1476-5381.2012.02054.X] [show BibTeX]  x  @article{RN24, author = {Faussner, A. and Schussler, S. and Feierler, J. and Bermudez, M. and Pfeifer, J. and Schnatbaum, K. and Tradler, T. and Jochum, M. and Wolber, G. and Gibson, C.}, title = {Binding characteristics of [3H]-JSM10292: a new cell membrane-permeant non-peptide bradykinin B2 receptor antagonist}, journal = {British Journal of Pharmacology}, volume = {167}, number = {4}, pages = {839-853}, ISSN = {0007-1188}, DOI = {Doi 10.1111/J.1476-5381.2012.02054.X}, url = {Go to ISI://WOS:000309396100013 http://onlinelibrary.wiley.com/store/10.1111/j.1476-5381.2012.02054.x/asset/j.1476-5381.2012.02054.x.pdf?v= 1&t=i0dnmrs5&s=0ec305f1063dfe790f7a2db2a4d72745d61a878e}, year = {2012}, abtract = {BACKGROUND AND PURPOSE A 3H-labelled derivative of the novel small-molecule bradykinin (BK) B2 receptor antagonist JSM10292 was used to directly study its binding properties to human and animal B2 receptors in intact cells and to closely define its binding site. EXPERIMENTAL APPROACH Equilibrium binding, dissociation and competition studies with various B2 receptor ligands and [3H]-JSM10292 were performed at 4 degrees C and 37 degrees C. The experiments were carried out using HEK293 cells stably (over)expressing wild-type and mutant B2 receptors of human and animal origin. KEY RESULTS [3H]-JSM10292 bound to B2 receptors at 4 degrees C and at 37 degrees C with the same high affinity. Its dissociation strongly depended on the temperature and increased when unlabelled B2 receptor agonists or antagonists were added. [3H]-JSM10292 is cell membrane-permeant and thus also bound to intracellular, active B2 receptors, as indicated by the different nonspecific binding in the presence of unlabelled JSM10292 or of membrane-impermeant BK. Equilibrium binding curves with [3H]-JSM10292 and competition experiments with unlabelled JSM10292 and [3H]-BK showed a different affinity profile for the wild-type B2 receptor in different species (man, cynomolgus, rabbit, mouse, rat, dog, pig, guinea pig). Characterization of B2 receptor mutants and species orthologues combined with homology modelling, using the CXCR4 as template, suggests that the binding site of JSM10292 is different from that of BK but overlaps with that of MEN16132, another small non-peptide B2 receptor ligand. CONCLUSIONS AND IMPLICATIONS [3H]-JSM10292 is a novel, cell membrane-permeant, high-affinity B2 receptor antagonist that allows direct in detail studies of active, surface and intracellularly located wild-type and mutant B2 receptors.}, type = {Journal Article}, keywords = {cell membrane-permeant radiolabelled non-peptide antagonist bradykinin b2 receptor small molecule compound binding site gpcr kinin b-2 receptor pharmacological characterization mutational analysis genetic algorithm helix 8 phosphorylation internalization pharmacophores sequestration recognition} }

[75]

L. Guasch, E. Sala, A. Castell-Auvi, L. Cedo, K. R. Liedl, G. Wolber, M. Muehlbacher, M. Mulero, M. Pinent, A. Ardevol, C. Valls, G. Pujadas, and S. Garcia-Vallve. Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation, Plos One, 7(11):, 2012.
Links: [doi:10.1371/journal.pone.0050816] [show BibTeX]  x  @article{RN22, author = {Guasch, L. and Sala, E. and Castell-Auvi, A. and Cedo, L. and Liedl, K. R. and Wolber, G. and Muehlbacher, M. and Mulero, M. and Pinent, M. and Ardevol, A. and Valls, C. and Pujadas, G. and Garcia-Vallve, S.}, title = {Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation}, journal = {Plos One}, volume = {7}, number = {11}, ISSN = {1932-6203}, DOI = {10.1371/journal.pone.0050816}, url = {Go to ISI://WOS:000312376100202 http://www.plosone.org/article/fetchObject.action?uri= info%3Adoi%2F10.1371%2Fjournal.pone.0050816&representation=PDF}, year = {2012}, abtract = {Background: Although there are successful examples of the discovery of new PPAR gamma agonists, it has recently been of great interest to identify new PPAR gamma partial agonists that do not present the adverse side effects caused by PPAR gamma full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPAR gamma partial agonists among natural products. Methodology/Principal Findings: We have developed a virtual screening procedure based on structure-based pharmacophore construction, protein-ligand docking and electrostatic/shape similarity to discover novel scaffolds of PPAR gamma partial agonists. From an initial set of 89,165 natural products and natural product derivatives, 135 compounds were identified as potential PPAR gamma partial agonists with good ADME properties. Ten compounds that represent ten new chemical scaffolds for PPAR gamma partial agonists were selected for in vitro biological testing, but two of them were not assayed due to solubility problems. Five out of the remaining eight compounds were confirmed as PPAR gamma partial agonists: they bind to PPAR gamma do not or only moderately stimulate the transactivation activity of PPAR gamma do not induce adipogenesis of preadipocyte cells and stimulate the insulin-induced glucose uptake of adipocytes. Conclusions/Significance: We have demonstrated that our virtual screening protocol was successful in identifying novel scaffolds for PPAR gamma partial agonists.}, type = {Journal Article}, keywords = {gamma partial agonists proliferator-activated-receptors ppar-gamma nuclear receptors drug discovery next-generation binding ligands modulators insights} }

[74]

J. Mortier, C. Rakers, R. Frederick, and G. Wolber. Computational Tools for In Silico Fragment-Based Drug Design, Curr Top Med Chem, 12(17):1935-1943, 2012.
Links: [show BibTeX]  x  @article{RN25, author = {Mortier, J. and Rakers, C. and Frederick, R. and Wolber, G.}, title = {Computational Tools for In Silico Fragment-Based Drug Design}, journal = {Current Topics in Medicinal Chemistry}, volume = {12}, number = {17}, pages = {1935-1943}, ISSN = {1568-0266}, url = {Go to ISI://WOS:000313429600009}, year = {2012}, abtract = {Fragment-based strategy in drug design involves the initial discovery of low-molecular mass molecules. Owing to their small-size, fragments are molecular tools to probe specific sub-pockets within a protein active site. Once their interaction within the enzyme cavity is clearly understood and experimentally validated, they represent a unique opportunity to design potent and efficient larger compounds. Computer-aided methods can essentially support the identification of suitable fragments. In this review, available tools for computational drug design are discussed in the frame of fragment-based approaches. We analyze and review (i) available commercial fragment libraries with respect to their properties and size, (ii) computational methods for the construction of such a library, (iii) the different strategies and software packages for the selection of the fragments with predicted affinity to a given target, and (iv) tools for the in silico linkage of fragments into an actual high-affinity lead structure candidate.}, type = {Journal Article}, keywords = {fragment-based design libraries software molecular modelling rule of three fragment linkage de-novo design protein active-sites lead discovery molecular complexity accurate docking combinatorial chemistry 3-dimensional structure receptor antagonists chemical fragments genetic algorithm} }

[73]

M. S. Murgueitio, M. Bermudez, J. Mortier, and G. Wolber. In silico virtual screening approaches for anti-viral drug discovery, Drug Discov Today Technol, 9(3):e219-25, 2012.
Links: [doi:10.1016/j.ddtec.2012.07.009] [show BibTeX]  x  @article{RN127, author = {Murgueitio, M. S. and Bermudez, M. and Mortier, J. and Wolber, G.}, title = {In silico virtual screening approaches for anti-viral drug discovery}, journal = {Drug Discov Today Technol}, volume = {9}, number = {3}, pages = {e219-25}, ISSN = {1740-6749 (Electronic) 1740-6749 (Linking)}, DOI = {10.1016/j.ddtec.2012.07.009}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24990575 http://ac.els-cdn.com/S1740674912000492/1-s2.0-S1740674912000492-main.pdf?_tid= cb79d2a2-4240-11e4-8cca-00000aacb360&acdnat=1411380858_da495ce55c81d16090c75028d80b953c}, year = {2012}, abtract = {Despite the considerable advances in medical and pharmaceutical research during the past years, diseases caused by viruses have remained a major burden to public health. Virtual in silico screening has repeatedly proven to be useful to meet the special challenges of antiviral drug discovery. Large virtual compound libraries are filtered by different computational screening methods such as docking, ligand-based similarity searches or pharmacophore-based screening, reducing the number of candidate molecules to a smaller set of promising candidates that are then tested biologically. This rational approach makes the drug discovery process more goal-oriented and saves resources in terms of time and money. In this review we discuss how different virtual screening techniques can be applied to antiviral drug discovery, present recent success stories in this field and finally address the main differences between the methods.:}, type = {Journal Article}, }

[72]

S. M. Noha, B. Jazzar, S. Kuehnl, J. M. Rollinger, H. Stuppner, A. M. Schaible, O. Werz, G. Wolber, and D. Schuster. Pharmacophore-based discovery of a novel cytosolic phospholipase A(2)alpha inhibitor, Bioorg Med Chem Lett, 22(2):1202-1207, 2012.
Links: [doi:10.1016/J.Bmcl.2011.11.093] [show BibTeX]  x  @article{RN36, author = {Noha, S. M. and Jazzar, B. and Kuehnl, S. and Rollinger, J. M. and Stuppner, H. and Schaible, A. M. and Werz, O. and Wolber, G. and Schuster, D.}, title = {Pharmacophore-based discovery of a novel cytosolic phospholipase A(2)alpha inhibitor}, journal = {Bioorganic & Medicinal Chemistry Letters}, volume = {22}, number = {2}, pages = {1202-1207}, ISSN = {0960-894X}, DOI = {Doi 10.1016/J.Bmcl.2011.11.093}, url = {Go to ISI://WOS:000299653500089 http://ac.els-cdn.com/S0960894X11016374/1-s2.0-S0960894X11016374-main.pdf?_tid= c508eafc-4240-11e4-831f-00000aacb362&acdnat=1411380847_7772547812e66f831632451579fb21ab}, year = {2012}, abtract = {The release of arachidonic acid, a precursor in the production of prostaglandins and leukotrienes, is achieved by activity of the cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Signaling mediated by this class of bioactive lipids, which are collectively referred to as eicosanoids, has numerous effects in physiological and pathological processes. Herein, we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the National Cancer Institute (NCI) database, leading to the identification of 4-(hexadecyloxy)-3-(2-(hydroxyimino)-3-oxobutanamido)benzoic acid (NSC 119957) as cPLA(2)alpha inhibitor in cell-free and cell-based in vitro assays. (C) 2011 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {cytosolic phospholipase a(2)alpha cpla(2)alpha inflammation pharmacophore modeling virtual screening in-vitro metabolic stability biological-activity a(2) inhibitors drug discovery design vivo lipophilicity solubility cells} }

[71]

R. Ottana, R. Maccari, S. Amuso, G. Wolber, D. Schuster, S. Herdlinger, G. Manao, G. Camici, and P. Paoli. New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells, Eur J Med Chem, 50:332-343, 2012.
Links: [doi:10.1016/J.Ejmech.2012.02.012] [show BibTeX]  x  @article{RN30, author = {Ottana, R. and Maccari, R. and Amuso, S. and Wolber, G. and Schuster, D. and Herdlinger, S. and Manao, G. and Camici, G. and Paoli, P.}, title = {New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells}, journal = {European Journal of Medicinal Chemistry}, volume = {50}, pages = {332-343}, ISSN = {0223-5234}, DOI = {Doi 10.1016/J.Ejmech.2012.02.012}, url = {Go to ISI://WOS:000303284400036 http://ac.els-cdn.com/S0223523412000888/1-s2.0-S0223523412000888-main.pdf?_tid= bdc34d1e-4240-11e4-9ceb-00000aacb35f&acdnat=1411380835_4d4b004d734d58a8eb4953f4383b947a}, year = {2012}, abtract = {In pursuing our research targeting the identification of potent inhibitors of PTP1B and LMW-PTP, we have identified new 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids endowed with interesting in vitro inhibitory profiles. Most compounds proved to be inhibitors of PTP1B and LMW-PTP isoform IF1. The tested inhibitors also showed selectivity towards PTP1B over the closely related TC-PTP. These compounds were found to activate the insulin-mediated signalling on mouse C2C12 skeletal muscle cells by increasing the phosphorylation levels of the insulin receptor and promoting cellular 2-deoxyglucose uptake. Interestingly, 4-{[5-(4-benzyloxybenzylidene)-2-(4-trifluoromethylphenylmino)-4-oxo-3-thiazolidinyl]methyl}benzoic acid (7d), the best in vitro inhibitor of PTP1B and the isoform IF1 of LMW-PTP, provided the highest activation level of the insulin receptor and was found to be endowed with an excellent insulinomimetic effect on the selected cells. This compound therefore represents an interesting lead compound for developing novel PTP1B and LMW-PTP inhibitors which could be achieved by improving both its pharmacological profile and its potentiating effects on insulin signalling. (C) 2012 Elsevier Masson SAS. All rights reserved.}, type = {Journal Article}, keywords = {enzyme inhibitor diabetes mellitus obesity protein tyrosine phosphatase insulinomimetic agent molecular docking weight phosphotyrosyl phosphatase structure-based optimization insulin sensitivity signal-transduction obese mice lmw-ptp negative regulator genetic algorithm crystal-structure 1b inhibitors} }

[70]

S. Santos-Sierra, J. Kirchmair, A. Perna, D. Reiss, K. Kemter, W. Roeschinger, H. Glossmann, S. Gersting, A. C. Muntau, G. Wolber, and F. B. Lagler. Discovery of Novel Pharmacological Chaperones for Pku That Correct Phenylketonuria in Vivo, J Inherit Metab Dis, 35:S3-S3, 2012.
Links: [show BibTeX]  x  @article{RN26, author = {Santos-Sierra, S. and Kirchmair, J. and Perna, A. and Reiss, D. and Kemter, K. and Roeschinger, W. and Glossmann, H. and Gersting, S. and Muntau, A. C. and Wolber, G. and Lagler, F. B.}, title = {Discovery of Novel Pharmacological Chaperones for Pku That Correct Phenylketonuria in Vivo}, journal = {Journal of Inherited Metabolic Disease}, volume = {35}, pages = {S3-S3}, ISSN = {0141-8955}, url = {Go to ISI://WOS:000307513100007}, year = {2012}, type = {Journal Article}, }

[69]

S. Santos-Sierra, J. Kirchmair, A. M. Perna, D. Reiss, K. Kemter, W. Roschinger, H. Glossmann, S. W. Gersting, A. C. Muntau, G. Wolber, and F. B. Lagler. Novel pharmacological chaperones that correct phenylketonuria in mice, Hum Mol Genet, 21(8):1877-1887, 2012.
Links: [doi:10.1093/Hmg/Dds001] [show BibTeX]  x  @article{RN29, author = {Santos-Sierra, S. and Kirchmair, J. and Perna, A. M. and Reiss, D. and Kemter, K. and Roschinger, W. and Glossmann, H. and Gersting, S. W. and Muntau, A. C. and Wolber, G. and Lagler, F. B.}, title = {Novel pharmacological chaperones that correct phenylketonuria in mice}, journal = {Human Molecular Genetics}, volume = {21}, number = {8}, pages = {1877-1887}, ISSN = {0964-6906}, DOI = {Doi 10.1093/Hmg/Dds001}, url = {Go to ISI://WOS:000302302400016 http://hmg.oxfordjournals.org/content/21/8/1877.full.pdf}, year = {2012}, abtract = {Phenylketonuria (PKU) is caused by inherited phenylalanine-hydroxylase (PAH) deficiency and, in many genotypes, it is associated with protein misfolding. The natural cofactor of PAH, tetrahydrobiopterin (BH4), can act as a pharmacological chaperone (PC) that rescues enzyme function. However, BH4 shows limited efficacy in some PKU genotypes and its chemical synthesis is very costly. Taking an integrated drug discovery approach which has not been applied to this target before, we identified alternative PCs for the treatment of PKU. Shape-focused virtual screening of the National Cancer Institutes chemical library identified 84 candidate molecules with potential to bind to the active site of PAH. An in vitro evaluation of these yielded six compounds that restored the enzymatic activity of the unstable PAHV106A variant and increased its stability in cell-based assays against proteolytic degradation. During a 3-day treatment study, two compounds (benzylhydantoin and 6-amino-5-(benzylamino)-uracil) substantially improved the in vivo Phe oxidation and blood Phe concentrations of PKU mice (Pah(enu1)). Notably, benzylhydantoin was twice as effective as tetrahydrobiopterin. In conclusion, we identified two PCs with high in vivo efficacy that may be further developed into a more effective drug treatment of PKU.}, type = {Journal Article}, keywords = {phenylalanine-hydroxylase deficiency surface-plasmon resonance neutral amino-acids ammonia-lyase mouse model in-vivo pyrimidine cofactors hepatoma-cells active-site tetrahydrobiopterin} }

[68]

A. Schafer, A. Wellner, M. Strauss, A. Schafer, G. Wolber, and R. Gust. Influence of Chlorine or Fluorine Substitution on the Estrogenic Properties of 1-Alkyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrroles, J Med Chem, 55(22):9607-9618, 2012.
Links: [show BibTeX]  x  @article{RN23, author = {Schafer, A. and Wellner, A. and Strauss, M. and Schafer, A. and Wolber, G. and Gust, R.}, title = {Influence of Chlorine or Fluorine Substitution on the Estrogenic Properties of 1-Alkyl-2,3,5-tris(4-hydroxyphenyl)-1H-pyrroles}, journal = {Journal of Medicinal Chemistry}, volume = {55}, number = {22}, pages = {9607-9618}, ISSN = {0022-2623}, url = {Go to ISI://WOS:000311461500017 http://pubs.acs.org/doi/pdfplus/10.1021/jm300860j}, year = {2012}, abtract = {In continuation of Our previous work, several 1- alkyl-2,3,5-tris(4-hydroxyphenyl)aryl-1H-pyrroles with chlor-Me or fluorine substituents in the aryl residues were synthesized and tested for estrogen receptor (ER) binding at isolated ER alpha/ER beta. receptors (HAP assay), and. in trans activation assays using ER alpha-positive MCF-7/2a as well as U2-OS/ER alpha and U2-OS/ER beta cells. In the competition experiment at ER alpha the compounds displayed very high relative binding-affinities of up to 37% (determined for 8m) but with restricted subtype selectivity (e.g., ER alpha/ER beta (8ma) = 9). The highest estrogenic potency in ER alpha-positive MCP-7/2a cells was determined for 2,3,5-tris(2-fluoro-4-hydroxyphenyl)-1-prolayl-1H-pyriole 8m (EC50 = 23 nM), while in U2-OS/ER alpha cells 2-(2-fluoro-4-hydroxyphenyl)-3,5-bis(4-hydroxyphenyl)-1H propyl-1H pyrrole 8b (EC50 = 0.12 nM) was the Most potent agonist, only 30 fold less active than estradiol (E2, EC50 = 0.004 nM). In U2-OS/ER beta cells for all pyrroles no transactivation could be observed, which indicates that they are selective ER alpha agonists in Cellular systems.}, type = {Journal Article}, keywords = {receptor-alpha er-beta breast-cancer mammary-gland binding mode mcf-7 cells part 5 ligands expression agonists} }

[67]

S. von Grafenstein, J. Mihaly-Bison, G. Wolber, V. N. Bochkov, K. R. Liedl, and D. Schuster. Identification of Novel Liver X Receptor Activators by Structure-Based Modeling, J Chem Inf Model, 52(5):1391-1400, 2012.
Links: [doi:10.1021/Ci300096c] [show BibTeX]  x  @article{RN28, author = {von Grafenstein, S. and Mihaly-Bison, J. and Wolber, G. and Bochkov, V. N. and Liedl, K. R. and Schuster, D.}, title = {Identification of Novel Liver X Receptor Activators by Structure-Based Modeling}, journal = {Journal of Chemical Information and Modeling}, volume = {52}, number = {5}, pages = {1391-1400}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci300096c}, url = {Go to ISI://WOS:000304385700030 http://pubs.acs.org/doi/pdfplus/10.1021/ci300096c}, year = {2012}, abtract = {Liver X receptors (LXRs) are members of the nuclear receptor family. Activators of LXRs are of high pharmacological interest as LXRs regulate cholesterol, fatty acid, and carbohydrate metabolism as well as inflammatory processes. On the basis of different X-ray crystal structures, we established a virtual screening workflow for the identification of novel LXR modulators. A two-step screening concept to identify active compounds included 3D-pharmacophore filters and rescoring by shape alignment. Eighteen virtual hits were tested in vitro applying a reporter gene assay, where concentration-dependent activity was proven for four novel lead structures. The most active compound 10, a 1,4-naphthochinone, has an estimated EC50 of around 5 mu M.}, type = {Journal Article}, keywords = {ligand-binding domain protein data-bank lxr-alpha crystal-structure immune-response tertiary-amines agonists beta discovery atherosclerosis} }

[66]

U. Grienke, J. M. Bison, D. Schuster, D. Guo, S. Guan, C. Cheng, V. N. Bochkov, B. R. Binder, G. Wolber, H. Stuppner, and J. M. Rollinger. In silico approaches to identify FXR-inducing constituents from Ganoderma lucidum - the Chinese mushroom of immortality, Planta Med, 77(12):1243-1244, 2011.
Links: [doi:10.1055/s-0031-1282129] [show BibTeX]  x  @article{RN42, author = {Grienke, U. and Bison, J. M. and Schuster, D. and Guo, D. and Guan, S. and Cheng, C. and Bochkov, V. N. and Binder, B. R. and Wolber, G. and Stuppner, H. and Rollinger, J. M.}, title = {In silico approaches to identify FXR-inducing constituents from Ganoderma lucidum - the Chinese mushroom of immortality}, journal = {Planta Medica}, volume = {77}, number = {12}, pages = {1243-1244}, ISSN = {0032-0943}, DOI = {10.1055/s-0031-1282129}, url = {Go to ISI://WOS:000294139000052}, year = {2011}, type = {Journal Article}, keywords = {farnesoid x receptor ganoderma lucidum lanostane triterpenes molecular modeling virtual screening natural products} }

[65]

U. Grienke, J. Mihaly-Bison, D. Schuster, T. Afonyushkin, M. Binder, S. H. Guan, C. R. Cheng, G. Wolber, H. Stuppner, D. A. Guo, V. N. Bochkov, and J. M. Rollinger. Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum, Bioorg Med Chem, 19(22):6779-6791, 2011.
Links: [doi:10.1016/J.Bmc.2011.09.039] [show BibTeX]  x  @article{RN39, author = {Grienke, U. and Mihaly-Bison, J. and Schuster, D. and Afonyushkin, T. and Binder, M. and Guan, S. H. and Cheng, C. R. and Wolber, G. and Stuppner, H. and Guo, D. A. and Bochkov, V. N. and Rollinger, J. M.}, title = {Pharmacophore-based discovery of FXR-agonists. Part II: Identification of bioactive triterpenes from Ganoderma lucidum}, journal = {Bioorganic & Medicinal Chemistry}, volume = {19}, number = {22}, pages = {6779-6791}, ISSN = {0968-0896}, DOI = {Doi 10.1016/J.Bmc.2011.09.039}, url = {Go to ISI://WOS:000296535900028 http://ac.els-cdn.com/S0968089611007747/1-s2.0-S0968089611007747-main.pdf?_tid= ecdb5704-4240-11e4-b338-00000aab0f6b&acdnat=1411380914_67b6f8e2669729c8ceaa125f56154535}, year = {2011}, abtract = {The farnesoid X receptor (FXR) belonging to the metabolic subfamily of nuclear receptors is a ligand-induced transcriptional activator. Its central function is the physiological maintenance of bile acid homeostasis including the regulation of glucose and lipid metabolism. Accessible structural information about its ligand-binding domain renders FXR an attractive target for in silico approaches. Integrated to natural product research these computational tools assist to find novel bioactive compounds showing beneficial effects in prevention and treatment of, for example, the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. Virtual screening experiments of our in-house Chinese Herbal Medicine database with structure-based pharmacophore models, previously generated and validated, revealed mainly lanostane-type triterpenes of the TCM fungus Ganoderma lucidum Karst. as putative FXR ligands. To verify the prediction of the in silico approach, two Ganoderma fruit body extracts and compounds isolated thereof were pharmacologically investigated. Pronounced FXR-inducing effects were observed for the extracts at a concentration of 100 mu g/mL. Intriguingly, five lanostanes out of 25 secondary metabolites from G. lucidum, that is, ergosterol peroxide (2), lucidumol A (11), ganoderic acid TR (12), ganodermanontriol (13), and ganoderiol F (14), dose-dependently induced FXR in the low micromolar range in a reporter gene assay. To rationalize the binding interactions, additional pharmacophore profiling and molecular docking studies were performed, which allowed establishing a first structure-activity relationship of the investigated triterpenes. (C) 2011 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {farnesoid x receptor ganoderma lucidum lanostane triterpenes ganoderic acids molecular modeling virtual screening natural products farnesoid-x-receptor bile-acid receptor natural-product guggulsterone orphan nuclear receptor hyperlipidemic rats gene-expression marine sponge potent ligand activation} }

[64]

J. Kirchmair, S. Distinto, K. R. Liedl, P. Markt, J. M. Rollinger, D. Schuster, G. M. Spitzer, and G. Wolber. Development of anti-viral agents using molecular modeling and virtual screening techniques, Infect Disord Drug Targets, 11(1):64-93, 2011.
Links: [doi:10.2174/187152611794407782] [show BibTeX]  x  @article{RN145, author = {Kirchmair, J. and Distinto, S. and Liedl, K. R. and Markt, P. and Rollinger, J. M. and Schuster, D. and Spitzer, G. M. and Wolber, G.}, title = {Development of anti-viral agents using molecular modeling and virtual screening techniques}, journal = {Infectious disorders drug targets}, volume = {11}, number = {1}, pages = {64-93}, ISSN = {2212-3989}, DOI = {10.2174/187152611794407782}, url = {http://www.eurekaselect.com/76753/article}, year = {2011}, type = {Journal Article}, }

[63]

D. V. Kratschmar, A. Vuorinen, T. Da Cunha, G. Wolber, D. Classen-Houben, O. Doblhoffe, D. Schuster, and A. Odermatt. Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11 beta-hydroxysteroid dehydrogenase type 2, J Steroid Biochem, 125(1-2):129-142, 2011.
Links: [doi:10.1016/J.Jsbmb.2010.12.019] [show BibTeX]  x  @article{RN45, author = {Kratschmar, D. V. and Vuorinen, A. and Da Cunha, T. and Wolber, G. and Classen-Houben, D. and Doblhoffe, O. and Schuster, D. and Odermatt, A.}, title = {Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11 beta-hydroxysteroid dehydrogenase type 2}, journal = {Journal of Steroid Biochemistry and Molecular Biology}, volume = {125}, number = {1-2}, pages = {129-142}, ISSN = {0960-0760}, DOI = {Doi 10.1016/J.Jsbmb.2010.12.019}, url = {Go to ISI://WOS:000292174400015 http://ac.els-cdn.com/S0960076011000057/1-s2.0-S0960076011000057-main.pdf?_tid= f070383a-4240-11e4-87eb-00000aab0f27&acdnat=1411380920_f9714622e17077fee892d66e6f45e49a}, year = {2011}, abtract = {Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18 beta-Glycyrrhetinic acid (GA), the biologically active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs). However, to assess the physiological functions of the respective enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11 beta-HSD1 and fifteen 11 beta-HSD2 inhibiting GA derivatives. Comparison of the GA derivatives in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11 beta-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11 beta-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11 beta-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11 beta-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biological activity of compounds was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11 beta-HSD1 or 11 beta-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivatives investigated. The most potent and selective 11 beta-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {11 beta-hydroxysteroid dehydrogenase glucocorticoid steroid metabolism inhibitor glycyrrhetinic acid pharmacophore 18-beta-glycyrrhetinic acid cell-proliferation 11-beta-hsd1 inhibitors selective inhibitors glucocorticoids expression arthritis rat hypertension cloning} }

[62]

S. M. Noha, A. G. Atanasov, D. Schuster, P. Markt, N. Fakhrudin, E. H. Heiss, O. Schrammel, J. M. Rollinger, H. Stuppner, V. M. Dirsch, and G. Wolber. Discovery of a novel IKK-beta inhibitor by ligand-based virtual screening techniques, Bioorg Med Chem Lett, 21(1):577-583, 2011.
Links: [doi:10.1016/J.Bmcl.2010.10.051] [show BibTeX]  x  @article{RN53, author = {Noha, S. M. and Atanasov, A. G. and Schuster, D. and Markt, P. and Fakhrudin, N. and Heiss, E. H. and Schrammel, O. and Rollinger, J. M. and Stuppner, H. and Dirsch, V. M. and Wolber, G.}, title = {Discovery of a novel IKK-beta inhibitor by ligand-based virtual screening techniques}, journal = {Bioorganic & Medicinal Chemistry Letters}, volume = {21}, number = {1}, pages = {577-583}, ISSN = {0960-894X}, DOI = {Doi 10.1016/J.Bmcl.2010.10.051}, url = {Go to ISI://WOS:000285544400122 http://ac.els-cdn.com/S0960894X1001512X/1-s2.0-S0960894X1001512X-main.pdf?_tid= e7822828-4240-11e4-9a26-00000aacb35e&acdnat=1411380905_15834d8aeb245e12d3dbba0e2b610014}, year = {2011}, abtract = {Various inflammatory stimuli that activate the nuclear factor kappa B (NF-kappa B) signaling pathway converge on a serine/threonine kinase that displays a key role in the activation of NF-kappa B: the I kappa beta Bkinase beta (IKK-beta). Therefore, IKK-beta is considered an interesting target for combating inflammation and cancer. In our study, we developed a ligand-based pharmacophore model for IKK-beta inhibitors. This model was employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored by molecular shape to rank and further prioritized virtual hits by three-dimensional shape-based alignment. One out of ten acquired and biologically tested compounds showed inhibitory activity in the low micromolar range on IKK-beta enzymatic activity in vitro and on NF-kappa B transactivation in intact cells. Compound 8 (2-(1-adamantyl) ethyl 4-[(2,5-dihydroxyphenyl) methylamino] benzoate) represents a novel chemical class of IKK-beta inhibitors and shows that the presented model is a valid approach for identification and development of new IKK-beta ligands. (C) 2010 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {i kappa b kinase beta ikk-beta virtual screening pharmacophore shape-based screening b kinase-beta nf-kappa-b small-molecule inhibitor hit-to-lead cancer-cells in-vitro inflammation design potent model} }

[61]

P. H. Pfisterer, C. X. Shen, Z. Nikolovska-Coleska, L. Schyschka, D. Schuster, A. Rudy, G. Wolber, A. M. Vollmar, J. M. Rollinger, and H. Stuppner. In silico discovery of acylated flavonol monorhamnosides from Eriobotrya japonica as natural, small-molecular weight inhibitors of XIAP BIR3, Bioorg Med Chem, 19(2):1002-1009, 2011.
Links: [doi:10.1016/J.Bmc.2010.10.046] [show BibTeX]  x  @article{RN49, author = {Pfisterer, P. H. and Shen, C. X. and Nikolovska-Coleska, Z. and Schyschka, L. and Schuster, D. and Rudy, A. and Wolber, G. and Vollmar, A. M. and Rollinger, J. M. and Stuppner, H.}, title = {In silico discovery of acylated flavonol monorhamnosides from Eriobotrya japonica as natural, small-molecular weight inhibitors of XIAP BIR3}, journal = {Bioorganic & Medicinal Chemistry}, volume = {19}, number = {2}, pages = {1002-1009}, ISSN = {0968-0896}, DOI = {Doi 10.1016/J.Bmc.2010.10.046}, url = {Go to ISI://WOS:000287590500031 http://ac.els-cdn.com/S0968089610009697/1-s2.0-S0968089610009697-main.pdf?_tid= e4826df4-4240-11e4-8d17-00000aab0f01&acdnat=1411380900_b468f81c63c984f71b8106b9f010a3a3}, year = {2011}, abtract = {Targeting the baculoviral inhibitor of apoptosis proteins repeat (BIR) 3 of X-linked inhibitor of apoptosis proteins (XIAP) represents an innovative strategy for the design of chemosensitizers. Acylated flavonol monorhamnosides (AFMR) from Eriobotrya japonica Lindl. (Rosaceae) were virtually predicted as ligands of the XIAP BIR3 domain by using a previously generated pharmacophore model. From the methanol leaf extract of E. japonica an enriched mixture of AFMR was obtained showing chemosensitizing potential in combination with etoposide in XIAP-overexpressing Jurkat cells. The HPLC-SPE-NMR hyphenated technique facilitated the structure elucidation of three known and two new natural AFMR. The main constituent and virtual hit, kaempferol-3-O-alpha-L-(2 '',4 ''-di-E-p-coumaroyl)-rhamnoside (3) was isolated from the enriched fraction. Applying a fluorescence polarization based binding assay, 3 was identified as XIAP BIR3 ligand with a dose-dependent affinity (IC(50) 10.4 mu M). Further, 3 induced apoptosis in XIAP-overexpressing Jurkat cells and activated caspase-9 in combination with etoposide. Docking experiments revealed a major impact of the coumaric acid and sugar moieties of 3 on XIAP BIR3 binding, which was experimentally confirmed. To conclude, this study elucidates 3 as natural, small-molecular weight XIAP BIR3 inhibitor using a combination of in silico and HPLC-SPE-NMR hyphenated techniques. (C) 2010 Published by Elsevier Ltd.}, type = {Journal Article}, keywords = {eriobotrya japonica molecular modeling xiap bir3 chemosensitizer resistant staphylococcus-aureus kaempferol induces apoptosis structure-based design x-linked inhibitor human glioma-cells laurus-nobilis protein xiap combinatorial chemistry mediated apoptosis down-regulation} }

[60]

A. Schafer, A. Wellner, M. Strauss, G. Wolber, and R. Gust. Development of 2,3,5-Triaryl-1H-pyrroles as Estrogen Receptor alpha Selective Ligands, ChemMedChem, 6(11):2055-2062, 2011.
Links: [doi:10.1002/Cmdc.201100283] [show BibTeX]  x  @article{RN40, author = {Schafer, A. and Wellner, A. and Strauss, M. and Wolber, G. and Gust, R.}, title = {Development of 2,3,5-Triaryl-1H-pyrroles as Estrogen Receptor alpha Selective Ligands}, journal = {Chemmedchem}, volume = {6}, number = {11}, pages = {2055-2062}, ISSN = {1860-7179}, DOI = {Doi 10.1002/Cmdc.201100283}, url = {Go to ISI://WOS:000297416900016 http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201100283/abstract http://onlinelibrary.wiley.com/store/10.1002/cmdc.201100283/asset/2055_ftp.pdf?v= 1&t=jdvm62xr&s=0a1c716ec030a5bbd99ce1333ff10b1162aab97b}, year = {2011}, abtract = {1-Alkyl-2,3,5-triaryl-1H-pyrroles (for which alkyl=methyl, ethyl, n-propyl, or 2-methylpropyl) were tested for stability, estrogen receptor (ER) binding, and inhibition of tumor cell growth. These pyrroles (type B) showed higher stability in aqueous solution than their 1,2,4-triaryl-1H-pyrrole congeners (type A pyrroles), exclusive ER alpha binding (no ER beta interaction), and a hormonal profile of partial agonists at ER alpha. The most potent compound, 1-(2-methylpropyl)-2,3,5-tris(4-hydroxyphenyl)-1H-pyrrole(5d), was less active than the lead structure 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) in MCF-7 cells stably transfected with the plasmid ERE(wtc)luc (MCF-7/2a), but more potent in U2-OS/alpha cells. Furthermore, 5d showed weak antiestrogenic properties (IC(50)= 310 nM). An additional propyl chain at C4 decreased the stability and pharmacological effects.}, type = {Journal Article}, keywords = {autoxidation cytotoxicity drug design hormones nitrogen heterocycles cancer cell-line biological evaluation binding mode pharmacophores substituents expression complexes agonists pattern protein} }

[59]

D. Schuster, D. Kowalik, J. Kirchmair, C. Laggner, P. Markt, C. Aebischer-Gumy, F. Strohle, G. Moller, G. Wolber, T. Wilckens, T. Langer, A. Odermatt, and J. Adamski. Identification of chemically diverse, novel inhibitors of 17 beta-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening, J Steroid Biochem, 125(1-2):148-161, 2011.
Links: [doi:10.1016/J.Jsbmb.2011.01.016] [show BibTeX]  x  @article{RN46, author = {Schuster, D. and Kowalik, D. and Kirchmair, J. and Laggner, C. and Markt, P. and Aebischer-Gumy, C. and Strohle, F. and Moller, G. and Wolber, G. and Wilckens, T. and Langer, T. and Odermatt, A. and Adamski, J.}, title = {Identification of chemically diverse, novel inhibitors of 17 beta-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening}, journal = {Journal of Steroid Biochemistry and Molecular Biology}, volume = {125}, number = {1-2}, pages = {148-161}, ISSN = {0960-0760}, DOI = {Doi 10.1016/J.Jsbmb.2011.01.016}, url = {Go to ISI://WOS:000292174400017 http://ac.els-cdn.com/S096007601100029X/1-s2.0-S096007601100029X-main.pdf?_tid= f36a6740-4240-11e4-8c6b-00000aacb362&acdnat=1411380925_0833b0aacfad662a3b491df135cdb746}, year = {2011}, abtract = {17 beta-Hydroxysteroid dehydrogenase type 3 and 5 (17 beta-HSD3 and 17 beta-HSD5) catalyze testosterone biosynthesis and thereby constitute therapeutic targets for androgen-related diseases or endocrine-disrupting chemicals. As a fast and efficient tool to identify potential ligands for 17 beta HSD3/5, ligand-and structure-based pharmacophore models for both enzymes were developed. The models were evaluated first by in silico screening of commercial compound databases and further experimentally validated by enzymatic efficacy tests of selected virtual hits. Among the 35 tested compounds, 11 novel inhibitors with distinct chemical scaffolds, e.g. sulfonamides and triazoles, and with different selectivity properties were discovered. Thereby, we provide several potential starting points for further 17 beta-HSD3 and 17 beta-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {pharmacophore screening inhibitor development steroid-dependent disease androgens estrogens prostaglandin-f-synthase nonsteroidal antiinflammatory drugs in-silico pharmacology keto reductase akr1c3 11-beta-hydroxysteroid dehydrogenases 20-alpha-hydroxysteroid dehydrogenase 4-hydroxyphenyl ketones biochemical evaluation crystal-structures discovery} }

[58]

D. Schuster, P. Markt, U. Grienke, J. Mihaly-Bison, M. Binder, S. M. Noha, J. M. Rollinger, H. Stuppner, V. N. Bochkov, and G. Wolber. Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation, Bioorg Med Chem, 19(23):7168-7180, 2011.
Links: [doi:10.1016/J.Bmc.2011.09.056] [show BibTeX]  x  @article{RN38, author = {Schuster, D. and Markt, P. and Grienke, U. and Mihaly-Bison, J. and Binder, M. and Noha, S. M. and Rollinger, J. M. and Stuppner, H. and Bochkov, V. N. and Wolber, G.}, title = {Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation}, journal = {Bioorganic & Medicinal Chemistry}, volume = {19}, number = {23}, pages = {7168-7180}, ISSN = {0968-0896}, DOI = {Doi 10.1016/J.Bmc.2011.09.056}, url = {Go to ISI://WOS:000296752300023 http://ac.els-cdn.com/S0968089611007917/1-s2.0-S0968089611007917-main.pdf?_tid= d9c96cf0-4240-11e4-b1af-00000aacb362&acdnat=1411380882_821a3ff30b0a83526fc8e74ae85a2ab4}, year = {2011}, abtract = {The farnesoid X receptor (FXR) is involved in glucose and lipid metabolism regulation, which makes it an attractive target for the metabolic syndrome, dyslipidemia, atherosclerosis, and type 2 diabetes. In order to find novel FXR agonists, a structure-based pharmacophore model collection was developed and theoretically evaluated against virtual databases including the ChEMBL database. The most suitable models were used to screen the National Cancer Institute (NCI) database. Biological evaluation of virtual hits led to the discovery of a novel FXR agonist with a piperazine scaffold (compound 19) that shows comparable activity as the endogenous FXR agonist chenodeoxycholic acid (CDCA, compound 2). (C) 2011 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {farnesoid x receptor molecular modeling virtual screening lead identification fxr agonist farnesoid-x-receptor bile-acid receptor nuclear receptor drug discovery potent identification antagonist activation database analogs} }

[57]

B. Waltenberger, D. Schuster, S. Paramapojn, W. Gritsanapan, G. Wolber, J. M. Rollinger, and H. Stuppner. Predicting cyclooxygenase inhibition by three-dimensional pharmacophoric profiling. Part II: Identification of enzyme inhibitors from Prasaplai, a Thai traditional medicine, Phytomedicine, 18(2-3):119-133, 2011.
Links: [doi:10.1016/J.Phymed.2010.08.002] [show BibTeX]  x  @article{RN48, author = {Waltenberger, B. and Schuster, D. and Paramapojn, S. and Gritsanapan, W. and Wolber, G. and Rollinger, J. M. and Stuppner, H.}, title = {Predicting cyclooxygenase inhibition by three-dimensional pharmacophoric profiling. Part II: Identification of enzyme inhibitors from Prasaplai, a Thai traditional medicine}, journal = {Phytomedicine}, volume = {18}, number = {2-3}, pages = {119-133}, ISSN = {0944-7113}, DOI = {Doi 10.1016/J.Phymed.2010.08.002}, url = {Go to ISI://WOS:000287767800005 http://ac.els-cdn.com/S0944711310002564/1-s2.0-S0944711310002564-main.pdf?_tid= d764b1cc-4240-11e4-8566-00000aacb361&acdnat=1411380878_04ee0e1144e9c8d4d34a03cb1fb4d185}, year = {2011}, abtract = {Prasaplai is a medicinal plant mixture that is used in Thailand to treat primary dysmenorrhea, which is characterized by painful uterine contractility caused by a significant increase of prostaglandin release. Cyclooxygenase (COX) represents a key enzyme in the formation of prostaglandins. Former studies revealed that extracts of Prasaplai inhibit COX-1 and COX-2. In this study, a comprehensive literature survey for known constituents of Prasaplai was performed. A multiconformational 3D database was created comprising 683 molecules. Virtual parallel screening using six validated pharmacophore models for COX inhibitors was performed resulting in a hit list of 166 compounds. 46 Prasaplai components with already determined COX activity were used for the external validation of this set of COX pharmacophore models. 57% of these components were classified correctly by the pharmacophore models. These findings confirm that the virtual approach provides a helpful tool (i) to unravel which molecular compounds might be responsible for the COX-inhibitory activity of Prasaplai and (ii) for the fast identification of novel COX inhibitors. (C) 2010 Elsevier GmbH. All rights reserved.}, type = {Journal Article}, keywords = {prasaplai traditional medicine of thailand natural products cyclooxygenase pharmacophore virtual screening cancer chemopreventive agents in-silico pharmacology drug discovery natural-products allium-sativum cox-2 inhibitors constituents seeds analogs acid} }

[56]

B. Waltenberger, K. Wiechmann, J. Bauer, P. Markt, S. M. Noha, G. Wolber, J. M. Rollinger, O. Werz, D. Schuster, and H. Stuppner. Pharmacophore Modeling and Virtual Screening for Novel Acidic Inhibitors of Microsomal Prostaglandin E-2 Synthase-1 (mPGES-1), J Med Chem, 54(9):3163-3174, 2011.
Links: [doi:10.1021/Jm101309g] [show BibTeX]  x  @article{RN44, author = {Waltenberger, B. and Wiechmann, K. and Bauer, J. and Markt, P. and Noha, S. M. and Wolber, G. and Rollinger, J. M. and Werz, O. and Schuster, D. and Stuppner, H.}, title = {Pharmacophore Modeling and Virtual Screening for Novel Acidic Inhibitors of Microsomal Prostaglandin E-2 Synthase-1 (mPGES-1)}, journal = {Journal of Medicinal Chemistry}, volume = {54}, number = {9}, pages = {3163-3174}, ISSN = {0022-2623}, DOI = {Doi 10.1021/Jm101309g}, url = {Go to ISI://WOS:000290126800003 http://pubs.acs.org/doi/pdfplus/10.1021/jm101309g}, year = {2011}, abtract = {Microsomal prostaglandin E-2 synthase-1 (mPGES-1) catalyzes prostaglandin E-2 formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC50 values between 0.4 and 7.9 mu M, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC50 values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGES-1 are presented that may possess anti-inflammatory properties based on the interference with eicosanoid biosynthesis.}, type = {Journal Article}, keywords = {therapeutic target 5-lipoxygenase inflammation 3d-qsar cancer cells} }

[55]

M. Enthammer, G. Wolber, H. Stuppner, M. Deutsch, and J. Troppmair. Targeting the BAG-1/Hsp70 axis to inhibit tumor growth, Febs J, 277:176-176, 2010.
Links: [show BibTeX]  x  @article{RN67, author = {Enthammer, M. and Wolber, G. and Stuppner, H. and Deutsch, M. and Troppmair, J.}, title = {Targeting the BAG-1/Hsp70 axis to inhibit tumor growth}, journal = {Febs Journal}, volume = {277}, pages = {176-176}, ISSN = {1742-464X}, url = {Go to ISI://WOS:000278565100618}, year = {2010}, type = {Journal Article}, }

[54]

N. Fakhrudin, A. Ladurner, A. Atanasov, E. Heiss, L. Baumgartner, P. Markt, D. Schuster, E. Ellmerer, G. Wolber, J. Rollinger, H. Stuppner, and V. Dirsch. Discovery and mechanistic characterization of neolignans as PPAR-gamma agonists, Febs J, 277:68-69, 2010.
Links: [show BibTeX]  x  @article{RN66, author = {Fakhrudin, N. and Ladurner, A. and Atanasov, A. and Heiss, E. and Baumgartner, L. and Markt, P. and Schuster, D. and Ellmerer, E. and Wolber, G. and Rollinger, J. and Stuppner, H. and Dirsch, V.}, title = {Discovery and mechanistic characterization of neolignans as PPAR-gamma agonists}, journal = {Febs Journal}, volume = {277}, pages = {68-69}, ISSN = {1742-464X}, url = {Go to ISI://WOS:000278565100248}, year = {2010}, type = {Journal Article}, }

[53]

N. Fakhrudin, A. Ladurner, A. G. Atanasov, E. H. Heiss, L. Baumgartner, P. Markt, D. Schuster, E. P. Ellmerer, G. Wolber, J. M. Rollinger, H. Stuppner, and V. M. Dirsch. Computer-Aided Discovery, Validation, and Mechanistic Characterization of Novel Neolignan Activators of Peroxisome Proliferator-Activated Receptor γ, Mol Pharmacol, 77(4):559-566, 2010.
Links: [doi:10.1124/mol.109.062141] [show BibTeX]  x  @article{RN146, author = {Fakhrudin, Nanang and Ladurner, Angela and Atanasov, Atanas G. and Heiss, Elke H. and Baumgartner, Lisa and Markt, Patrick and Schuster, Daniela and Ellmerer, Ernst P. and Wolber, Gerhard and Rollinger, Judith M. and Stuppner, Hermann and Dirsch, Verena M.}, title = {Computer-Aided Discovery, Validation, and Mechanistic Characterization of Novel Neolignan Activators of Peroxisome Proliferator-Activated Receptor γ}, journal = {Molecular Pharmacology}, volume = {77}, number = {4}, pages = {559-566}, DOI = {10.1124/mol.109.062141}, url = {http://molpharm.aspetjournals.org/content/77/4/559.abstract http://molpharm.aspetjournals.org/content/77/4/559.full.pdf}, year = {2010}, abtract = {Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used for the treatment of type 2 diabetes and metabolic syndrome. However, the currently used PPARγ agonists display serious side effects, which has led to a great interest in the discovery of novel ligands with favorable properties. The aim of our study was to identify new PPARγ agonists by a PPARγ pharmacophore–based virtual screening of 3D natural product libraries. This in silico approach led to the identification of several neolignans predicted to bind the receptor ligand binding domain (LBD). To confirm this prediction, the neolignans dieugenol, tetrahydrodieugenol, and magnolol were isolated from the respective natural source or synthesized and subsequently tested for PPARγ receptor binding. The neolignans bound to the PPARγ LBD with EC50 values in the nanomolar range, exhibiting a binding pattern highly similar to the clinically used agonist pioglitazone. In intact cells, dieugenol and tetrahydrodieugenol selectively activated human PPARγ-mediated, but not human PPARα- or -β/δ-mediated luciferase reporter expression, with a pattern suggesting partial PPARγ agonism. The coactivator recruitment study also demonstrated partial agonism of the tested neolignans. Dieugenol, tetrahydrodieugenol, and magnolol but not the structurally related eugenol induced 3T3-L1 preadipocyte differentiation, confirming effectiveness in a cell model with endogenous PPARγ expression. In conclusion, we identified neolignans as novel ligands for PPARγ, which exhibited interesting activation profiles, recommending them as potential pharmaceutical leads or dietary supplements.}, type = {Journal Article}, }

[52]

M. Goebel, G. Wolber, P. Markt, B. Staels, T. Unger, U. Kintscher, and R. Gust. Characterization of new PPAR gamma agonists: Benzimidazole derivatives-importance of positions 5 and 6, and computational studies on the binding mode, Bioorg Med Chem, 18(16):5885-5895, 2010.
Links: [doi:10.1016/J.Bmc.2010.06.102] [show BibTeX]  x  @article{RN59, author = {Goebel, M. and Wolber, G. and Markt, P. and Staels, B. and Unger, T. and Kintscher, U. and Gust, R.}, title = {Characterization of new PPAR gamma agonists: Benzimidazole derivatives-importance of positions 5 and 6, and computational studies on the binding mode}, journal = {Bioorganic & Medicinal Chemistry}, volume = {18}, number = {16}, pages = {5885-5895}, ISSN = {0968-0896}, DOI = {Doi 10.1016/J.Bmc.2010.06.102}, url = {Go to ISI://WOS:000280664100011 http://ac.els-cdn.com/S0968089610006309/1-s2.0-S0968089610006309-main.pdf?_tid= 1dbbb09e-4241-11e4-974e-00000aacb361&acdnat=1411380996_1a144cf8b6d634f437abc795aa808c95}, year = {2010}, abtract = {In this and previous studies we investigated the importance of partial structures of Telmisartan on PPAR gamma activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl) methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d] imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPAR gamma DEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPAR gamma activation. An enhanced effect on PPAR gamma activation could be observed if lipophilic moieties are introduced in these positions. 4 '-[(2-Propyl-1H-naphtho[2,3-d] imidazol-1-yl) methyl] biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC(50) of 0.26 mu M and the profile of a full agonist. Together with compounds of the former structure-activity relationship study (position 2-substituted benzimidazole derivatives 4a-4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments. (C) 2010 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {benzimidazole derivatives partial agonism selective ppar gamma modulators structure-activity relationship molecular modeling proliferator-activated receptors molecular recognition biological evaluation fatty-acids alpha ligands pharmacophores metabolites discovery} }

[51]

U. Grienke, M. Schmidtke, J. Kirchmair, K. Pfarr, P. Wutzler, R. Durrwald, G. Wolber, K. R. Liedl, H. Stuppner, and J. M. Rollinger. Antiviral Potential and Molecular Insight into Neuraminidase Inhibiting Diarylheptanoids from Alpinia katsumadai, J Med Chem, 53(2):778-786, 2010.
Links: [doi:10.1021/Jm901440f] [show BibTeX]  x  @article{RN73, author = {Grienke, U. and Schmidtke, M. and Kirchmair, J. and Pfarr, K. and Wutzler, P. and Durrwald, R. and Wolber, G. and Liedl, K. R. and Stuppner, H. and Rollinger, J. M.}, title = {Antiviral Potential and Molecular Insight into Neuraminidase Inhibiting Diarylheptanoids from Alpinia katsumadai}, journal = {Journal of Medicinal Chemistry}, volume = {53}, number = {2}, pages = {778-786}, ISSN = {0022-2623}, DOI = {Doi 10.1021/Jm901440f}, url = {Go to ISI://WOS:000273672100024 http://pubs.acs.org/doi/pdfplus/10.1021/jm901440f}, year = {2010}, abtract = {At present, neuraminidase (NA) inhibitors are the mainstay of pharmacological strategies to fight against global pandemic influenza. In the search for new antiviral drug leads from nature, the seed extract of Alpinia katsumadai has been phytochemically investigated. Among the six isolated constituents, four diarylheptanoids showed in vitro NA inhibitory activities in low micromolar ranges against human influenza virus A/PR/8/34 of subtype H(1)N(1). The most promising constituent, katsumadain A (4; IC(50) = 1.05 +/- 0.42 mu M), also inhibited the NA of Four H(1)N(1) swine influenza viruses, with IC(50) values between 0.9 and 1.64 mu M, and showed antiviral effects in plaque reduction assays. Considering the flexible loop regions of NA, extensive molecular dynamics (MD) simulations were performed to study the putative binding mechanism of the T-shaped diarylheptanoid 4. Docking results showed well-established interactions between the protein and the core of this novel NA-inhibiting natural scaffold, excellent surface complementarity to the simulated binding pocket, and concordance with experimentally derived SAR data.}, type = {Journal Article}, keywords = {influenza-a-viruses oseltamivir-resistant influenza amantadine resistance adamantane resistance drug design emergence dynamics germany h1n1 surveillance} }

[50]

L. G. Nashev, D. Schuster, C. Laggner, S. Sodha, T. Langer, G. Wolber, and A. Odermatt. The UV-filter benzophenone-1 inhibits 17 beta-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals, Biochem Pharmacol, 79(8):1189-1199, 2010.
Links: [doi:10.1016/J.Bcp.2009.12.005] [show BibTeX]  x  @article{RN70, author = {Nashev, L. G. and Schuster, D. and Laggner, C. and Sodha, S. and Langer, T. and Wolber, G. and Odermatt, A.}, title = {The UV-filter benzophenone-1 inhibits 17 beta-hydroxysteroid dehydrogenase type 3: Virtual screening as a strategy to identify potential endocrine disrupting chemicals}, journal = {Biochemical Pharmacology}, volume = {79}, number = {8}, pages = {1189-1199}, ISSN = {0006-2952}, DOI = {Doi 10.1016/J.Bcp.2009.12.005}, url = {Go to ISI://WOS:000275391400014 http://ac.els-cdn.com/S0006295209010624/1-s2.0-S0006295209010624-main.pdf?_tid= 1318166e-4241-11e4-ab41-00000aacb35e&acdnat=1411380978_cdb785e0811ed886426510660287dd66}, year = {2010}, abtract = {The prevalence of male reproductive disorders and testicular cancer is steadily increasing. Because the exposure to chemicals disrupting natural hormone action has been associated with these diseases, it is important to identify endocrine disrupting chemicals (EDCs) and their targets of action. Here, a 3D-structural database that can be applied for virtual screening approaches to facilitate the identification of EDCs was constructed. The database was screened using pharmacophores of 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3), which catalyzes the last step of testosterone synthesis in testicular Leydig cells and plays an essential role during male sexual development. Among other chemicals, benzophenone (BP) UV-filters were predicted as potential 17 beta-HSD3 inhibitors. Biological analyses revealed (2,4-dihydroxyphenyl)-phenylmethanone (also known as benzophenone-1, BP-1) as an inhibitor of human 17 beta-HSD3 (IC50 1.05 mu M). BP-1 also efficiently blocked conversion of androstenedione to testosterone by mouse and rat 17 beta-HSD3 in whole-organ enzyme assays. Moreover, BP-I antagonized the testosterone-dependent activation of androgen receptors (IC50 5.7 mu M), suggesting synergistic anti-androgenic effects of BP-1 by preventing testosterone formation and blocking receptor activation. In addition, analyses of several commonly used UV-filters on estrogen- and androgen-metabolizing 17 beta-HSD enzymes revealed 3-benzylidene camphor (3-BC) and 4-methylbenzylidene camphor (4-MBC) as low micromolar 17 beta-HSD2 inhibitors. In conclusion, screening of virtual chemical structure libraries can facilitate the identification of compounds interfering with hormone action. The potential disruption of 17 beta-HSD enzyme function by the UV-filters BP-1, 3-BC and 4-MBC requires further investigation and should be considered for safety assessment of these chemicals. (C) 2009 Elsevier Inc. All rights reserved.}, type = {Journal Article}, keywords = {17 beta-hydroxysteroid dehydrogenase androgen testosterone endocrine disruptor pharmacophore virtual screening uv-filter body topical application developmental toxicity estrogenic activity surface waters swiss lakes derivatives phthalate fish identification sunscreens} }

[49]

P. Pfisterer, Z. Nikolovska-Coleska, L. Schyschka, D. Schuster, A. Rudy, G. Wolber, A. Vollmar, J. Rollinger, and H. Stuppner. Acylated flavonol monorhamnosides from Eriobotrya japonica as XIAP BIR3 inhibitors revealed by in silica and HPLC-SPE-NMR techniques, Planta Med, 76(12):1344-1345, 2010.
Links: [doi:10.1055/s-0030-1264888] [show BibTeX]  x  @article{RN63, author = {Pfisterer, P. and Nikolovska-Coleska, Z. and Schyschka, L. and Schuster, D. and Rudy, A. and Wolber, G. and Vollmar, A. and Rollinger, J. and Stuppner, H.}, title = {Acylated flavonol monorhamnosides from Eriobotrya japonica as XIAP BIR3 inhibitors revealed by in silica and HPLC-SPE-NMR techniques}, journal = {Planta Medica}, volume = {76}, number = {12}, pages = {1344-1345}, ISSN = {0032-0943}, DOI = {10.1055/s-0030-1264888}, url = {Go to ISI://WOS:000282066500709}, year = {2010}, type = {Journal Article}, keywords = {apoptosis} }

[48]

P. H. Pfisterer, G. Wolber, T. Efferth, J. M. Rollinger, and H. Stuppner. Natural products in structure-assisted design of molecular cancer therapeutics, Curr Pharm Design, 16(15):1718-1741, 2010.
Links: [doi:10.2174/138161210791164027] [show BibTeX]  x  @article{RN68, author = {Pfisterer, P. H. and Wolber, G. and Efferth, T. and Rollinger, J. M. and Stuppner, H.}, title = {Natural products in structure-assisted design of molecular cancer therapeutics}, journal = {Current Pharmaceutical Design}, volume = {16}, number = {15}, pages = {1718-1741}, ISSN = {1381-6128}, DOI = {10.2174/138161210791164027}, url = {Go to ISI://WOS:000277126000007 http://www.eurekaselect.com/71574/article}, year = {2010}, abtract = {Since the late 1990's, novel insights into molecular biology and carcinogenesis enabled the rational design of mechanismbased anticancer therapeutics. The large number of natural product (NP)-derived drugs currently under clinical evaluation and the recent approval of temsirolimus (Torisel (R)) as a first mTOR protein kinase inhibitor indicate that NPs have to be considered not only as a seminal source of cytotoxic, but also as a source of molecularly targeted agents. Whereas molecular modeling is well established as an important and successful method to discover and rationalize bioactivities in medicinal chemistry research, its application has proven to be also a powerful tool in the field of NPs. This review highlights the impact of computer-assisted approaches on NPs as molecularly targeted anticancer drugs. Examples of applications are provided focusing on innovative targets such as protein kinases, tumour vasculature, epigenetic modulators, heat shock protein (Hsp) 90, and direct apoptosis enhancers.}, type = {Journal Article}, keywords = {natural product phytochemicals cancer drug discovery in silico techniques molecular modeling virtual screening docking histone deacetylase inhibitors x-linked inhibitor tyrosine kinase inhibitors growth-factor receptor microtubule-stabilizing agents traditional chinese medicine containing hydroxamic acids constrained smac mimetics structure-based discovery apoptotic bcl-2 proteins} }

[47]

J. Rollinger, D. Kratschmar, D. Schuster, P. Pfisterer, S. Brandstotter, H. Stuppner, G. Wolber, and A. Odermatt. In silico access for the discovery of 11 beta-HSD 1 inhibiting triterpenes from Eriobotrya japonica, Planta Med, 76(12):1181-1181, 2010.
Links: [doi:10.1055/s-0030-1264252] [show BibTeX]  x  @article{RN61, author = {Rollinger, J. and Kratschmar, D. and Schuster, D. and Pfisterer, P. and Brandstotter, S. and Stuppner, H. and Wolber, G. and Odermatt, A.}, title = {In silico access for the discovery of 11 beta-HSD 1 inhibiting triterpenes from Eriobotrya japonica}, journal = {Planta Medica}, volume = {76}, number = {12}, pages = {1181-1181}, ISSN = {0032-0943}, DOI = {10.1055/s-0030-1264252}, url = {Go to ISI://WOS:000282066500073}, year = {2010}, type = {Journal Article}, }

[46]

J. M. Rollinger, D. V. Kratschmar, D. Schuster, P. H. Pfisterer, C. Gumy, E. M. Aubry, S. Brandstotter, H. Stuppner, G. Wolber, and A. Odermatt. 11 beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches, Bioorg Med Chem, 18(4):1507-1515, 2010.
Links: [doi:10.1016/J.Bmc.2010.01.010] [show BibTeX]  x  @article{RN72, author = {Rollinger, J. M. and Kratschmar, D. V. and Schuster, D. and Pfisterer, P. H. and Gumy, C. and Aubry, E. M. and Brandstotter, S. and Stuppner, H. and Wolber, G. and Odermatt, A.}, title = {11 beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches}, journal = {Bioorganic & Medicinal Chemistry}, volume = {18}, number = {4}, pages = {1507-1515}, ISSN = {0968-0896}, DOI = {Doi 10.1016/J.Bmc.2010.01.010}, url = {Go to ISI://WOS:000274425500016 http://ac.els-cdn.com/S0968089610000295/1-s2.0-S0968089610000295-main.pdf?_tid= 07b1dcce-4241-11e4-a26d-00000aab0f6c&acdnat=1411380959_65bcb9a54c995606feea5afea87bb4fd}, year = {2010}, abtract = {The inhibition of 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1), which catalyzes the conversion of inactive 11-ketoglucocorticoids to active 11 beta-hydroxyglucocorticoids, emerged as promising strategy to treat symptoms of the metabolic syndrome, including obesity and type 2 diabetes. In this study the leaves of the anti-diabetic medicinal plant loquat (Eriobotrya japonica) were phytochemically investigated following hints from a pharmacophore-based virtual screening and a bioactivity-guided approach. Determination of the 11 beta-HSD1 and 11 beta-HSD2 inhibitory activities in cell lysates revealed triterpenes from the ursane type as selective, low micro-molar inhibitors of 11 beta-HSD1, that is, corosolic acid (1), 3-epicorosolic acid methyl ester (4), 2-alpha hydroxy-3-oxo urs-12-en-28-oic acid (6), tormentic acid methyl ester (8), and ursolic acid (9). Importantly, a mixture of loquat constituents with moderate activities displayed a pronounced additive effect. By means of molecular modeling studies and the identification of the 11 beta-HSD1-inhibiting 11-keto-ursolic acid (17) and 3-acetyl-11-keto-ursolic acid (18) a structure -activity relationship was deduced for this group of pentacyclic triterpenes. The mechanism of action elucidated in the present work together with the previously determined pharmacological activities provides these natural products with an astonishing multi-targeted anti-diabetic profile. (C) 2010 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {eriobotrya japonica 11 beta-hsd1 diabetes glucocorticoid receptor metabolic syndrome occurring pentacyclic triterpenes corosolic acid folium-eriobotryae metabolic syndrome diabetes-mellitus type-1 inhibitors protein leaves pharmacophores glycosides} }

[45]

R. Rubbiani, I. Kitanovic, H. Alborzinia, S. Can, A. Kitanovic, L. A. Onambele, M. Stefanopoulou, Y. Geldmacher, W. S. Sheldrick, G. Wolber, A. Prokop, S. Wolfl, and I. Ottt. Benzimidazol-2-ylidene Gold(I) Complexes Are Thioredoxin Reductase Inhibitors with Multiple Antitumor Properties, J Med Chem, 53(24):8608-8618, 2010.
Links: [doi:10.1021/Jm100801e] [show BibTeX]  x  @article{RN54, author = {Rubbiani, R. and Kitanovic, I. and Alborzinia, H. and Can, S. and Kitanovic, A. and Onambele, L. A. and Stefanopoulou, M. and Geldmacher, Y. and Sheldrick, W. S. and Wolber, G. and Prokop, A. and Wolfl, S. and Ottt, I.}, title = {Benzimidazol-2-ylidene Gold(I) Complexes Are Thioredoxin Reductase Inhibitors with Multiple Antitumor Properties}, journal = {Journal of Medicinal Chemistry}, volume = {53}, number = {24}, pages = {8608-8618}, ISSN = {0022-2623}, DOI = {Doi 10.1021/Jm100801e}, url = {Go to ISI://WOS:000285264300014 http://pubs.acs.org/doi/pdfplus/10.1021/jm100801e}, year = {2010}, abtract = {Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands 1a-4a represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by 1a-4a in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex (2a) revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.}, type = {Journal Article}, keywords = {n-heterocyclic carbene antimicrobial activity phosphine-ligands metal-complexes cancer-cells mitochondria pharmacophores ruthenium(ii) cytotoxicity chemistry} }

[44]

D. Schuster, L. Kern, D. P. Hristozov, L. Terfloth, B. Bienfait, C. Laggner, J. Kirchmair, U. Grienke, G. Wolber, T. Langer, H. Stuppner, J. Gasteiger, and J. M. Rollinger. Applications of Integrated Data Mining Methods to Exploring Natural Product Space for Acetylcholinesterase Inhibitors, Combinatorial Chemistry & High Throughput Screening, 13(1):54-66, 2010.
Links: [show BibTeX]  x  @article{RN75, author = {Schuster, D. and Kern, L. and Hristozov, D. P. and Terfloth, L. and Bienfait, B. and Laggner, C. and Kirchmair, J. and Grienke, U. and Wolber, G. and Langer, T. and Stuppner, H. and Gasteiger, J. and Rollinger, J. M.}, title = {Applications of Integrated Data Mining Methods to Exploring Natural Product Space for Acetylcholinesterase Inhibitors}, journal = {Combinatorial Chemistry & High Throughput Screening}, volume = {13}, number = {1}, pages = {54-66}, ISSN = {1386-2073}, url = {Go to ISI://WOS:000274021800007}, year = {2010}, abtract = {Nature, especially the plant kingdom, is a rich source for novel bioactive compounds that can be used as lead compounds for drug development. In order to exploit this resource, the two neural network-based virtual screening techniques novelty detection with self-organizing maps (SOMs) and counterpropagation neural network were evaluated as tools for efficient lead structure discovery. As application scenario, significant descriptors for acetylcholinesterase (AChE) inhibitors were determined and used for model building, theoretical model validation, and virtual screening. Top-ranked virtual hits from both approaches were docked into the AChE binding site to approve the initial hits. Finally, in vitro testing of selected compounds led to the identification of forsythoside A and (+)-sesamolin as novel AChE inhibitors.}, type = {Journal Article}, keywords = {natural products drug discovery acetylcholinesterase virtual screening counterpropagation network spinne novelty detection active-site gorge torpedo-californica acetylcholinesterase in-silico pharmacology novelty detection neural-networks drug discovery counterpropagation networks infrared-spectra protein binding} }

[43]

D. Schuster, M. Spetea, M. Music, S. Rief, M. Fink, J. Kirchmair, J. Schutz, G. Wolber, T. Langer, H. Stuppner, H. Schmidhammer, and J. M. Rollinger. Morphinans and isoquinolines: Acetylcholinesterase inhibition, pharmacophore modeling, and interaction with opioid receptors, Bioorg Med Chem, 18(14):5071-5080, 2010.
Links: [doi:10.1016/J.Bmc.2010.05.071] [show BibTeX]  x  @article{RN64, author = {Schuster, D. and Spetea, M. and Music, M. and Rief, S. and Fink, M. and Kirchmair, J. and Schutz, J. and Wolber, G. and Langer, T. and Stuppner, H. and Schmidhammer, H. and Rollinger, J. M.}, title = {Morphinans and isoquinolines: Acetylcholinesterase inhibition, pharmacophore modeling, and interaction with opioid receptors}, journal = {Bioorganic & Medicinal Chemistry}, volume = {18}, number = {14}, pages = {5071-5080}, ISSN = {0968-0896}, DOI = {Doi 10.1016/J.Bmc.2010.05.071}, url = {Go to ISI://WOS:000279744700025 http://ac.els-cdn.com/S096808961000502X/1-s2.0-S096808961000502X-main.pdf?_tid= 16953092-4241-11e4-9a26-00000aacb35e&acdnat=1411380984_f0779c4eeef7c816ebcd45393f5b7194}, year = {2010}, abtract = {Following indications from pharmacophore-based virtual screening of natural product databases, morphinan and isoquinoline compounds were tested in vitro for acetylcholinesterase (AChE) inhibition. After the first screen, active and inactive compounds were used to build a ligand-based pharmacophore model in order to prioritize compounds for biological testing. Among the virtual hits tested, the enrichment of actives was significantly higher than in a random selection of test compounds. The most active compounds were biochemically tested for their activity on mu, delta, and kappa opioid receptors. (C) 2010 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {morphinans acetylcholinesterase inhibition opioid receptor pharmacophore modeling lead structure discovery in-silico pharmacology biological evaluation drug discovery natural-products highly potent 14-alkoxymorphinans agonist derivatives binding} }

[42]

D. Schuster, B. Waltenberger, J. Kirchmair, S. Distinto, P. Markt, H. Stuppner, J. M. Rollinger, and G. Wolber. Predicting Cyclooxygenase Inhibition by Three-Dimensional Pharmacophoric Profiling. Part I: Model Generation, Validation and Applicability in Ethnopharmacology, Mol Inf, 29(1-2):75-86, 2010.
Links: [doi:10.1002/Minf.200900071] [show BibTeX]  x  @article{RN74, author = {Schuster, D. and Waltenberger, B. and Kirchmair, J. and Distinto, S. and Markt, P. and Stuppner, H. and Rollinger, J. M. and Wolber, G.}, title = {Predicting Cyclooxygenase Inhibition by Three-Dimensional Pharmacophoric Profiling. Part I: Model Generation, Validation and Applicability in Ethnopharmacology}, journal = {Molecular Informatics}, volume = {29}, number = {1-2}, pages = {75-86}, ISSN = {1868-1743}, DOI = {Doi 10.1002/Minf.200900071}, url = {Go to ISI://WOS:000275879300008 http://onlinelibrary.wiley.com/store/10.1002/minf.200900071/asset/75_ftp.pdf?v= 1&t=i0dnol2q&s=71943a78fb1d037012a4867a156bf738e3a4cf5c}, year = {2010}, abtract = {3D pharmacophore modeling has evolved as an established and state-of-the-art method for performing in-silico predictions of biological activity. Using one single model is limited to single binding modes, while the combination of several models bears a broader application scope. We demonstrate the generation of a complete and predictive 3D model set for cyclooxygenase 1 and 2 inhibitors, along with a selection and validation protocol optimized for parallel virtual screening. This model set was applied to explain the cyclooxygenase activity of an ethnopharmacologically known mixture of natural products, the Thai traditional medicine "Prasaplai". Results show that rationalizing natural product activity by modern in-silico approaches is promising and can be tremendously useful in the identification of the mechanisms of action for known biological effects of complex herbal remedies.}, type = {Journal Article}, keywords = {molecular modeling parallel screening cyclooxygenase inhibitors ethnopharmacology prasaplai medicinal chemistry molecular modeling prostaglandin h-2 synthase high-throughput docking drug discovery cox-2 inhibitors silico pharmacology natural-products ppar ligands chemistry optimization constituents} }

[41]

D. Schuster, and G. Wolber. Identification of bioactive natural products by pharmacophore-based virtual screening, Curr Pharm Design, 16(15):1666-1681, 2010.
Links: [doi:10.2174/138161210791164072] [show BibTeX]  x  @article{RN69, author = {Schuster, D. and Wolber, G.}, title = {Identification of bioactive natural products by pharmacophore-based virtual screening}, journal = {Current Pharmaceutical Design}, volume = {16}, number = {15}, pages = {1666-1681}, ISSN = {1381-6128}, DOI = {10.2174/138161210791164072}, url = {Go to ISI://WOS:000277126000003 http://www.eurekaselect.com/71570/article}, year = {2010}, abtract = {Natural products have been exposed to a long selection process to interact with biological targets and are therefore a valuable source for ideas for novel chemical entities in drug development. However, the process to determine activities of natural products is mainly based on serendipity, and can thus become time- and cost-intensive. In this review we present strategies on how modern in-silico molecular modeling techniques can be used to make this process more efficient and discuss how to discover and optimize drug candidates inspired by nature. Focusing on 3D pharmacophore modeling techniques, we provide an overview of virtual screening and modeling methods, review available in silico databases as sources for chemical structures of natural products, discuss techniques for biological activity profiling, and summarize recent success stories for the combination of in-silico approaches and pharmacognosy.}, type = {Journal Article}, keywords = {pharmacophore modeling virtual screening natural products natural product databases parallel screening 11-beta-hydroxysteroid dehydrogenase type-1 relationship 3d/4d-qsar analyses bound ligand conformations rhinovirus coat protein high-throughput docking in-silico pharmacology drug discovery medicinal chemistry historical-perspective compound libraries} }

[40]

D. Schuster, and G. Wolber. Pharmacophore-guided elucidation of the active principle from natural compounds, Planta Med, 76(12):1179-1179, 2010.
Links: [doi:10.1055/s-0030-1264244] [show BibTeX]  x  @article{RN60, author = {Schuster, D. and Wolber, G.}, title = {Pharmacophore-guided elucidation of the active principle from natural compounds}, journal = {Planta Medica}, volume = {76}, number = {12}, pages = {1179-1179}, ISSN = {0032-0943}, DOI = {10.1055/s-0030-1264244}, url = {Go to ISI://WOS:000282066500065}, year = {2010}, type = {Journal Article}, }

[39]

A. M. Scutaru, M. Wenzel, H. Scheffler, G. Wolber, and R. Gust. Optimization of the N-Lost Drugs Melphalan and Bendamustine: Synthesis and Cytotoxicity of a New Set of Dendrimer-Drug Conjugates as Tumor Therapeutic Agents, Bioconjug Chem, 21(10):1728-1743, 2010.
Links: [doi:10.1021/Bc900453f] [show BibTeX]  x  @article{RN56, author = {Scutaru, A. M. and Wenzel, M. and Scheffler, H. and Wolber, G. and Gust, R.}, title = {Optimization of the N-Lost Drugs Melphalan and Bendamustine: Synthesis and Cytotoxicity of a New Set of Dendrimer-Drug Conjugates as Tumor Therapeutic Agents}, journal = {Bioconjugate Chemistry}, volume = {21}, number = {10}, pages = {1728-1743}, ISSN = {1043-1802}, DOI = {Doi 10.1021/Bc900453f}, url = {Go to ISI://WOS:000283101000004 http://pubs.acs.org/doi/pdfplus/10.1021/bc900453f}, year = {2010}, abtract = {Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3-aminopropyl)-N-(3-{3,5-bis[3-{3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB-231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2-hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro.}, type = {Journal Article}, keywords = {human serum-albumin in-vitro efficacy cancer-chemotherapy protein-binding breast-cancer cell-lines delivery macromolecules chlorambucil hydrolysis} }

[38]

T. Seidel, G. Ibis, F. Bendix, and G. Wolber. Strategies for 3D pharmacophore-based virtual screening, Drug Discovery Today: Technologies, 7(4):e221-e228, 2010.
Links: [doi:10.1016/j.ddtec.2010.11.004] [show BibTeX]  x  @article{RN149, author = {Seidel, Thomas and Ibis, Gökhan and Bendix, Fabian and Wolber, Gerhard}, title = {Strategies for 3D pharmacophore-based virtual screening}, journal = {Drug Discovery Today: Technologies}, volume = {7}, number = {4}, pages = {e221-e228}, ISSN = {1740-6749}, DOI = {10.1016/j.ddtec.2010.11.004}, url = {http://www.sciencedirect.com/science/article/pii/S1740674910000375 http://ac.els-cdn.com/S1740674910000375/1-s2.0-S1740674910000375-main.pdf?_tid= a44c90c2-4338-11e4-b35e-00000aab0f26&acdnat=1411487308_5e2a9c8b80c22ea886bffb40225bf767}, year = {2010}, abtract = {3D pharmacophore-based techniques have become one of the most important approaches for the fast and accurate virtual screening of databases with millions of compounds. The success of 3D pharmacophores is largely based on their intuitive interpretation and creation, but the virtual screening with such three-dimensional geometric models still poses a considerable algorithmic and conceptual challenge. Most current implementations favor fast screening speed at the detriment of accuracy. This review describes the general strategies and algorithms employed for 3D pharmacophore searching by some current pharmacophore modeling platforms and will highlight their differences.}, type = {Journal Article}, }

[37]

G. M. Spitzer, M. Heiss, M. Mangold, P. Mark, J. Kirchmair, G. Wolber, and K. R. Liedl. One Concept, Three Implementations of 3D Pharmacophore-Based Virtual Screening: Distinct Coverage of Chemical Search Space, J Chem Inf Model, 50(7):1241-1247, 2010.
Links: [doi:10.1021/Ci100136b] [show BibTeX]  x  @article{RN65, author = {Spitzer, G. M. and Heiss, M. and Mangold, M. and Mark, P. and Kirchmair, J. and Wolber, G. and Liedl, K. R.}, title = {One Concept, Three Implementations of 3D Pharmacophore-Based Virtual Screening: Distinct Coverage of Chemical Search Space}, journal = {Journal of Chemical Information and Modeling}, volume = {50}, number = {7}, pages = {1241-1247}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci100136b}, url = {Go to ISI://WOS:000280183200005 http://pubs.acs.org/doi/pdfplus/10.1021/ci100136b}, year = {2010}, abtract = {Feature-based pharmacophore modeling is a well-established concept to support early stage drug discovery, where large virtual databases are filtered for potential drug candidates. The concept is implemented in popular molecular modeling software, including Catalyst, Phase, and MOE. With these software tools we performed a comparative virtual screening campaign on HSP90 and FXIa, taken from the 'maximum unbiased validation' data set. Despite the straightforward concept that pharmacophores are based on, we observed an unexpectedly high degree of variation among the hit lists obtained. By harmonizing the pharmacophore feature definitions of the investigated approaches, the exclusion volume sphere settings, and the screening parameters, we have derived a rationale for the observed differences, providing insight on the strengths and weaknesses of these algorithms. Application of more than one of these software tools in parallel will result in a widened coverage of chemical space. This is not only rooted in the dissimilarity of feature definitions but also in different algorithmic search strategies.}, type = {Journal Article}, keywords = {3-d pharmacophores molecular docking hsp90 inhibitors factor xia database protein discovery design phase sets} }

[36]

B. Waltenberger, D. Schuster, S. Paramapojn, W. Gritsanapan, G. Wolber, J. Rollinger, and H. Stuppner. In silico strategy for the identification of cyclooxygenase inhibitors from the Thai medicinal mixture Prasaplai, Planta Med, 76(12):1173-1173, 2010.
Links: [doi:10.1055/s-0030-1264217] [show BibTeX]  x  @article{RN62, author = {Waltenberger, B. and Schuster, D. and Paramapojn, S. and Gritsanapan, W. and Wolber, G. and Rollinger, J. and Stuppner, H.}, title = {In silico strategy for the identification of cyclooxygenase inhibitors from the Thai medicinal mixture Prasaplai}, journal = {Planta Medica}, volume = {76}, number = {12}, pages = {1173-1173}, ISSN = {0032-0943}, DOI = {10.1055/s-0030-1264217}, url = {Go to ISI://WOS:000282066500038}, year = {2010}, type = {Journal Article}, }

[35]

G. Wolber. 3D pharmacophore elucidation and virtual screening, Drug Discovery Today: Technologies, 7(4):e203-e204, 2010.
Links: [doi:10.1016/j.ddtec.2010.12.004] [show BibTeX]  x  @article{RN148, author = {Wolber, Gerhard}, title = {3D pharmacophore elucidation and virtual screening}, journal = {Drug Discovery Today: Technologies}, volume = {7}, number = {4}, pages = {e203-e204}, ISSN = {1740-6749}, DOI = {10.1016/j.ddtec.2010.12.004}, url = {http://www.sciencedirect.com/science/article/pii/S1740674910000594 http://ac.els-cdn.com/S1740674910000594/1-s2.0-S1740674910000594-main.pdf?_tid= 9d9770c6-4338-11e4-8e98-00000aab0f26&acdnat=1411487297_6c73913aac983d10bbaefbbd42d854c2}, year = {2010}, type = {Journal Article}, }

[34]

D. Classen-Houben, D. Schuster, T. Da Cunha, A. Odermatt, G. Wolber, U. Jordis, and B. Kueenburg. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase 1 by 18 alpha-glycyrrhetinic acid but not 18 beta-glycyrrhetinic acid, J Steroid Biochem, 113(3-5):248-252, 2009.
Links: [doi:10.1016/J.Jsbmb.2009.01.009] [show BibTeX]  x  @article{RN80, author = {Classen-Houben, D. and Schuster, D. and Da Cunha, T. and Odermatt, A. and Wolber, G. and Jordis, U. and Kueenburg, B.}, title = {Selective inhibition of 11 beta-hydroxysteroid dehydrogenase 1 by 18 alpha-glycyrrhetinic acid but not 18 beta-glycyrrhetinic acid}, journal = {Journal of Steroid Biochemistry and Molecular Biology}, volume = {113}, number = {3-5}, pages = {248-252}, ISSN = {0960-0760}, DOI = {Doi 10.1016/J.Jsbmb.2009.01.009}, url = {Go to ISI://WOS:000264667700015 http://ac.els-cdn.com/S0960076009000235/1-s2.0-S0960076009000235-main.pdf?_tid= 3fb59e94-4241-11e4-9940-00000aacb35e&acdnat=1411381053_e5218dc0338bb5180ca2156369c587b7}, year = {2009}, abtract = {Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active Ilp-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11 beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18 beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11 beta-HSD1 and 11 beta-HSD2. Here, we compare the biological activity of 18 beta-GA and its diastereomer 18 alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18 alpha-GA selectively inhibits 11 beta-HSD1 but not 11 beta-HSD2. This is in contrast to 18 beta-GA, which preferentially inhibits 11 beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11 beta-HSD1, we provide an explanation for the differences in the activities of 18 alpha-GA and 18 beta-GA. This model will be used to design novel selective derivatives of GA. (C) 2009 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {glycyrrhetinic acid 11beta-hydroxysteroid dehydrogenase 11 beta-hsd glucocorticoid inhibitor ligandscout pharmacophore model metabolic syndrome glycyrrhetic acid type-1 derivatives obesity pharmacophores variability sensitivity metabolism reductase receptor} }

[33]

J. Kirchmair, S. Distinto, P. Markt, D. Schuster, G. M. Spitzer, K. R. Liedl, and G. Wolber. How To Optimize Shape-Based Virtual Screening: Choosing the Right Query and Including Chemical Information, J Chem Inf Model, 49(3):678-692, 2009.
Links: [doi:10.1021/Ci8004226] [show BibTeX]  x  @article{RN79, author = {Kirchmair, J. and Distinto, S. and Markt, P. and Schuster, D. and Spitzer, G. M. and Liedl, K. R. and Wolber, G.}, title = {How To Optimize Shape-Based Virtual Screening: Choosing the Right Query and Including Chemical Information}, journal = {Journal of Chemical Information and Modeling}, volume = {49}, number = {3}, pages = {678-692}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci8004226}, url = {Go to ISI://WOS:000264533400016 http://pubs.acs.org/doi/pdfplus/10.1021/ci8004226}, year = {2009}, abtract = {Shape-based molecular similarity approaches have been established as important and popular virtual screening techniques. Recent applications have shown successful screening campaigns using different parameters and query selection. It is common sense that pure volume overlap scoring (or "shape-based screening") under-represents chemical or pharmacophoric information of a molecule. Using the "Directory of Useful Decoys" (DUD) as a benchmark set, we systematically evaluate how (i) the choice of query conformations, (ii) the selection of the active compound to be used as a query structure, and (iii) the inclusion of chemical information (i.e., the pharmacophoric properties of the query molecule) affect screening performance. Varying these parameters bears remarkable potential for improvements and delivers the best screening performance reported using these tools so far. From these insights, guidelines on how to reach optimum performance during virtual screening are developed.}, type = {Journal Article}, keywords = {high-throughput docking hiv entry inhibitors molecular shape pharmacophore models drug discovery data fusion similarity recognition performance efficiency} }

[32]

P. Markt, C. Feldmann, J. M. Rollinger, S. Raduner, D. Schuster, J. Kirchmair, S. Distinto, G. M. Spitzer, G. Wolber, C. Laggner, K. H. Altmann, T. Langer, and J. Gertsch. Discovery of Novel CB2 Receptor Ligands by a Pharmacophore-Based Virtual Screening Workflow, J Med Chem, 52(2):369-378, 2009.
Links: [doi:10.1021/Jm801044g] [show BibTeX]  x  @article{RN82, author = {Markt, P. and Feldmann, C. and Rollinger, J. M. and Raduner, S. and Schuster, D. and Kirchmair, J. and Distinto, S. and Spitzer, G. M. and Wolber, G. and Laggner, C. and Altmann, K. H. and Langer, T. and Gertsch, J.}, title = {Discovery of Novel CB2 Receptor Ligands by a Pharmacophore-Based Virtual Screening Workflow}, journal = {Journal of Medicinal Chemistry}, volume = {52}, number = {2}, pages = {369-378}, ISSN = {0022-2623}, DOI = {Doi 10.1021/Jm801044g}, url = {Go to ISI://WOS:000262522100016 http://pubs.acs.org/doi/pdfplus/10.1021/jm801044g}, year = {2009}, abtract = {Cannabinoid receptor 2 (CB2 receptor) ligands are potential candidates for the therapy of chronic pain, inflammatory disorders, atherosclerosis, and osteoporosis. We describe the development of pharmacophore models for CB2 receptor ligands, as well as a pharmacophore-based virtual screening workflow, which resulted in 14 hits for experimental follow-up. Seven compounds were identified with K-i values below 25 mu M. The CB2 receptor-selective pyridine tetrahydrocannabinol analogue 8 (K-i = 1.78 mu M) was identified as a CB2 partial agonist. Acetamides 12 (K-i = 1.35 mu M) and 18 (K-i = 2.1 mu M) represent new scaffolds for CB2 receptor-selective antagonists and inverse agonists, respectively. Overall, our pharmacophore-based workflow yielded three novel scaffolds for the chemical development of CB2 receptor ligands.}, type = {Journal Article}, keywords = {peripheral cannabinoid receptor selective agonists docking analysis homology models derivatives antagonist inhibitors potent pharmacology protein} }

[31]

A. Perdih, A. Kovac, G. Wolber, D. Blanot, S. Gobec, and T. Solmajer. Discovery of novel benzene 1,3-dicarboxylic acid inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach, Bioorg Med Chem Lett, 19(10):2668-2673, 2009.
Links: [doi:10.1016/J.Bmcl.2009.03.141] [show BibTeX]  x  @article{RN77, author = {Perdih, A. and Kovac, A. and Wolber, G. and Blanot, D. and Gobec, S. and Solmajer, T.}, title = {Discovery of novel benzene 1,3-dicarboxylic acid inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach}, journal = {Bioorganic & Medicinal Chemistry Letters}, volume = {19}, number = {10}, pages = {2668-2673}, ISSN = {0960-894X}, DOI = {Doi 10.1016/J.Bmcl.2009.03.141}, url = {Go to ISI://WOS:000265627800012 http://ac.els-cdn.com/S0960894X09004636/1-s2.0-S0960894X09004636-main.pdf?_tid= 43459adc-4241-11e4-9734-00000aab0f26&acdnat=1411381059_aed1d3bb32f8155b76efdb290240e17c}, year = {2009}, abtract = {The peptidoglycan biosynthetic pathway provides an array of potential targets for antibacterial drug design, attractive especially with respect to selective toxicity. Within this pathway, the members of the Mur ligase family are considered as promising emerging targets for novel antibacterial drug design. Based on the available MurD crystal structures co-crystallised with N-sulfonyl glutamic acid inhibitors, a virtual screening campaign was performed, combining three-dimensional structure-based pharmacophores and molecular docking calculations. A novel class of glutamic acid surrogates-benzene 1,3-dicarboxylic acid derivatives-were identified and compounds 14 and 16 found to possess dual MurD and MurE inhibitory activity. (C) 2009 Elsevier Ltd. All rights reserved.}, type = {Journal Article}, keywords = {murd and mure enzymes virtual screening three-dimensional structure-based pharmacophores molecular docking antibacterial agents drug design biosynthesis enzymes murd cell-wall biosynthesis alanyl-d-glutamate peptidoglycan biosynthesis escherichia-coli phosphinate inhibitors l-alanine pharmacophores derivatives phosphate} }

[30]

J. M. Rollinger, D. Schuster, B. Danzl, S. Schwalger, P. Markt, M. Schmidtke, J. Gertsch, S. Raduner, G. Wolber, T. Langer, and H. Stuppner. In silico Target Fishing for Rationalized Ligand Discovery Exemplified on Constituents of Ruta graveolens, Planta Med, 75(3):195-204, 2009.
Links: [doi:10.1055/S-0028-1088397] [show BibTeX]  x  @article{RN81, author = {Rollinger, J. M. and Schuster, D. and Danzl, B. and Schwalger, S. and Markt, P. and Schmidtke, M. and Gertsch, J. and Raduner, S. and Wolber, G. and Langer, T. and Stuppner, H.}, title = {In silico Target Fishing for Rationalized Ligand Discovery Exemplified on Constituents of Ruta graveolens}, journal = {Planta Medica}, volume = {75}, number = {3}, pages = {195-204}, ISSN = {0032-0943}, DOI = {Doi 10.1055/S-0028-1088397}, url = {Go to ISI://WOS:000264061000001 https://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0028-1088397.pdf}, year = {2009}, abtract = {The identification of targets whose interaction is likely to result in the successful treatment of a disease is of growing interest for natural product scientists. In the Current Study we performed an exemplary application of a virtual parallel screening approach to identify potential targets for 16 secondary metabolites isolated and identified from the aerial parts of the medicinal plant Ruta graveolens L. Low energy conformers of the isolated constituents were simultaneously screened against a set of 2208 pharmacophore models generated in-house for the in silico prediction of putative biological targets, i.e., target fishing, Based on the predicted ligand-target interactions, we focused on three biological targets, namely acetylcholinesterase (AChE), the human rhinovirus (HRV) coat protein and the cannabinoid receptor type-2 (CB(2)). For a critical evaluation of the applied parallel screening approach, virtual hits and non-hits were assayed on the respective targets. For AChE the highest scoring virtual hit, arborinine, showed the best inhibitory in vitro activity on AChE (IC(50) 34.7 mu M). Determination of the anti-HRV-2 effect revealed 6,7,8-trimethoxycoumarin and arborinine to be the most active antiviral constituents with IC(50) values of 11.98 mu M and 3.19 mu M, respectively. Of these, arborinine was predicted virtually. Of all the molecules subjected to parallel screening, one virtual CB(2) ligand was obtained, i.e., rutamarin. Interestingly, in experimental Studies only this compound showed a selective activity to the CB(2) receptor (Ki of 7.4 mu M) by using a radioligand displacement assay. The applied parallel screening paradigm with constituents of R. graveolens on three different proteins has shown promise as an in silico tool for rational target fishing and pharmacological profiling of extracts and single chemical entities in natural product research.}, type = {Journal Article}, keywords = {ruta graveolens l. rutaceae pharmacophore modelling virtual parallel screening acetylcholinesterase cannabinoid receptor 2 human rhinovirus coat protein rhinovirus coat protein natural-products acetylcholinesterase inhibitors quinoline alkaloids drug discovery pharmacology derivatives bioactivity wirkstoffe coumarin} }

[29]

P. Tiikkainen, P. Markt, G. Wolber, J. Kirchmair, S. Distinto, A. Poso, and O. Kallioniemi. Critical Comparison of Virtual Screening Methods against the MUV Data Set, J Chem Inf Model, 49(10):2168-2178, 2009.
Links: [doi:10.1021/Ci900249b] [show BibTeX]  x  @article{RN76, author = {Tiikkainen, P. and Markt, P. and Wolber, G. and Kirchmair, J. and Distinto, S. and Poso, A. and Kallioniemi, O.}, title = {Critical Comparison of Virtual Screening Methods against the MUV Data Set}, journal = {Journal of Chemical Information and Modeling}, volume = {49}, number = {10}, pages = {2168-2178}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci900249b}, url = {Go to ISI://WOS:000271011500003 http://pubs.acs.org/doi/pdfplus/10.1021/ci900249b}, year = {2009}, abtract = {In the current work, we measure the performance of seven ligand-based virtual screening tools - five similarity search methods and two pharmacophore elucidators - against the MUV data set. For the similarity search tools, single active molecules as well as active compound sets clustered in terms of their chemical diversity were used as templates., Their score was calculated against all inactive and active compounds in their target class. Subsequently, the scores were used to calculate different performance metrics in eluding enrichment factors and AUC values. We also studied the effect of data fusion on the results. To measure the performance of the pharmacophore tools, a set of active molecules was picked either random- or chemical diversity-based from each target class to build a pharmacophore model which was then used to screen the remaining compounds in the set. Our results indicate that template sets selected by their chemical diversity are the best choice for similarity search tools, whereas the optimal training sets for pharmacophore elucidators are based on random selection underscoring that pharmacophore modeling cannot be easily automated. We also suggest a number of improvements for future benchmark sets and discuss activity cliffs as a potential problem in ligand-based virtual screening.}, type = {Journal Article}, keywords = {body molecular superposition similarity function data fusion optimization docking brutus shape} }

[28]

J. Kirchmair, S. Distinto, D. Schuster, G. Spitzer, T. Langer, and G. Wolber. Enhancing drug discovery through in silico screening: Strategies to increase true positives retrieval rates, Curr Med Chem, 15(20):2040-2053, 2008.
Links: [doi:10.2174/092986708785132843] [show BibTeX]  x  @article{RN90, author = {Kirchmair, J. and Distinto, S. and Schuster, D. and Spitzer, G. and Langer, T. and Wolber, G.}, title = {Enhancing drug discovery through in silico screening: Strategies to increase true positives retrieval rates}, journal = {Current Medicinal Chemistry}, volume = {15}, number = {20}, pages = {2040-2053}, ISSN = {0929-8673}, DOI = {Doi 10.2174/092986708785132843}, url = {Go to ISI://WOS:000258754800004 http://www.eurekaselect.com/67389/article}, year = {2008}, abtract = {Computational chemistry software for lead discovery has become well established in pharmaceutical industry and has found its way to the desktop computers of medicinal chemists for different purposes, providing insight on the mode of action and binding properties, and creating new ideas for lead structure refinement. In this review we investigate the performance and reliability of recent state-of-the-art data modeling techniques, as well as ligand-based and structure-based modeling approaches for 3D virtual screening. We discuss and summarize recently published success stories and lately developed techniques. Parallel screening is one of these emerging approaches allowing for efficient activity in silico profiling of several compounds against different targets or anti-targets simultaneously. This is of special interest to medicinal chemists, as the approach allows revealing unknown binding modes ('target-fishing') as well as integrated ADME profiling or - more generally - the prediction of off-target effects.}, type = {Journal Article}, keywords = {data modeling virtual screening parallel screening adme/tox profiling activity profiling target fishing pharmacophore modeling protein-ligand docking molecular-field analysis 3-dimensional quantitative structure protein-ligand interactions support vector machines torsade-de-pointes pharmacophore identification 3d qsar receptor antagonists coupled receptors lead generation} }

[27]

J. Kirchmair, P. Markt, S. Distinto, D. Schuster, G. M. Spitzer, K. R. Liedl, T. Langer, and G. Wolber. The Protein Data Bank (PDB), Its Related Services and Software Tools as Key Components for In Silico Guided Drug Discovery, J Med Chem, 51(22):7021-7040, 2008.
Links: [doi:10.1021/Jm8005977] [show BibTeX]  x  @article{RN83, author = {Kirchmair, J. and Markt, P. and Distinto, S. and Schuster, D. and Spitzer, G. M. and Liedl, K. R. and Langer, T. and Wolber, G.}, title = {The Protein Data Bank (PDB), Its Related Services and Software Tools as Key Components for In Silico Guided Drug Discovery}, journal = {Journal of Medicinal Chemistry}, volume = {51}, number = {22}, pages = {7021-7040}, ISSN = {0022-2623}, DOI = {Doi 10.1021/Jm8005977}, url = {Go to ISI://WOS:000261056600001 http://pubs.acs.org/doi/pdfplus/10.1021/jm8005977}, year = {2008}, type = {Journal Article}, keywords = {ligand-binding-sites web-accessible database structural genomics structure alignment crystal-structures molecular docking force-field x-ray functional annotation automatic-generation} }

[26]

J. Kirchmair, P. Markt, S. Distinto, G. Wolber, and T. Langer. Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection - What can we learn from earlier mistakes?, J Comput Aided Mol Des, 22(3-4):213-228, 2008.
Links: [doi:10.1007/S10822-007-9163-6] [show BibTeX]  x  @article{RN96, author = {Kirchmair, J. and Markt, P. and Distinto, S. and Wolber, G. and Langer, T.}, title = {Evaluation of the performance of 3D virtual screening protocols: RMSD comparisons, enrichment assessments, and decoy selection - What can we learn from earlier mistakes?}, journal = {Journal of Computer-Aided Molecular Design}, volume = {22}, number = {3-4}, pages = {213-228}, ISSN = {0920-654X}, DOI = {Doi 10.1007/S10822-007-9163-6}, url = {Go to ISI://WOS:000254249000011 http://download.springer.com/static/pdf/2/art%253A10.1007%252Fs10822-007-9163-6.pdf?auth66= 1411553689_abca80d2ea67a9f6fee936fbdcf3f65a&ext=.pdf}, year = {2008}, abtract = {Within the last few years a considerable amount of evaluative studies has been published that investigate the performance of 3D virtual screening approaches. Thereby, in particular assessments of protein-ligand docking are facing remarkable interest in the scientific community. However, comparing virtual screening approaches is a non-trivial task. Several publications, especially in the field of molecular docking, suffer from shortcomings that are likely to affect the significance of the results considerably. These quality issues often arise from poor study design, biasing, by using improper or inexpressive enrichment descriptors, and from errors in interpretation of the data output. In this review we analyze recent literature evaluating 3D virtual screening methods, with focus on molecular docking. We highlight problematic issues and provide guidelines on how to improve the quality of computational studies. Since 3D virtual screening protocols are in general assessed by their ability to discriminate between active and inactive compounds, we summarize the impact of the composition and preparation of test sets on the outcome of evaluations. Moreover, we investigate the significance of both classic enrichment parameters and advanced descriptors for the performance of 3D virtual screening methods. Furthermore, we review the significance and suitability of RMSD as a measure for the accuracy of protein-ligand docking algorithms and of conformational space sub sampling algorithms.}, type = {Journal Article}, keywords = {virtual screening evaluation of computational methods pharmacophore modeling protein-ligand docking enrichment descriptors decoy selection virtual library design tautomerism rmsd protein-ligand docking high-throughput docking incremental construction algorithm automated molecular docking library design drug design pharmacophore models chemical similarity genetic algorithm scoring functions} }

[25]

P. Markt, C. McGoohan, B. Walker, J. Kirchmair, C. L. Feldmann, G. De Martino, G. Spitzer, S. Distinto, D. Schuster, G. Wolber, C. Laggner, and T. Langer. Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening, J Chem Inf Model, 48(8):1693-1705, 2008.
Links: [doi:10.1021/Ci800101j] [show BibTeX]  x  @article{RN91, author = {Markt, P. and McGoohan, C. and Walker, B. and Kirchmair, J. and Feldmann, C. L. and De Martino, G. and Spitzer, G. and Distinto, S. and Schuster, D. and Wolber, G. and Laggner, C. and Langer, T.}, title = {Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening}, journal = {Journal of Chemical Information and Modeling}, volume = {48}, number = {8}, pages = {1693-1705}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci800101j}, url = {Go to ISI://WOS:000258697400015 http://pubs.acs.org/doi/pdfplus/10.1021/ci800101j}, year = {2008}, abtract = {The cysteine protease cathepsin S (CatS) is involved in the pathogenesis of autoimmune disorders, atherosclerosis, and obesity. Therefore, it represents a promising pharmacological target for drug development. We generated ligand-based and structure-based pharmacophore models for noncovalent and covalent CatS inhibitors to perform virtual high-throughput screening of chemical databases in order to discover novel scaffolds for CatS inhibitors. An in vitro evaluation of the resulting 15 structures revealed seven CatS inhibitors with kinetic constants in the low micromolar range. These compounds can be subjected to further chemical modifications to obtain drugs for the treatment of autoimmune disorders and atherosclerosis.}, type = {Journal Article}, keywords = {k inhibitors noncovalent inhibitors arylaminoethyl amides cysteine proteases design potent docking binding models series} }

[24]

P. Markt, R. K. Petersen, E. N. Flindt, K. Krjstiansen, J. Kirchmair, G. Spitzer, S. Distinto, D. Schuster, G. Wolber, C. Laggner, and T. Langer. Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening, J Med Chem, 51(20):6303-6317, 2008.
Links: [doi:10.1021/Jm800128k] [show BibTeX]  x  @article{RN85, author = {Markt, P. and Petersen, R. K. and Flindt, E. N. and Krjstiansen, K. and Kirchmair, J. and Spitzer, G. and Distinto, S. and Schuster, D. and Wolber, G. and Laggner, C. and Langer, T.}, title = {Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening}, journal = {Journal of Medicinal Chemistry}, volume = {51}, number = {20}, pages = {6303-6317}, ISSN = {0022-2623}, DOI = {Doi 10.1021/Jm800128k}, url = {Go to ISI://WOS:000260102700008 http://pubs.acs.org/doi/pdfplus/10.1021/jm800128k}, year = {2008}, abtract = {Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.}, type = {Journal Article}, keywords = {proliferator-activated-receptor fatty-acids in-vitro delta gamma antagonist alpha agonist drugs} }

[23]

D. Schuster, L. G. Nashev, J. Kirchmair, C. Laggner, G. Wolber, T. Langer, and A. Odermatt. Discovery of nonsteroidal 17 beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries, J Med Chem, 51(14):4188-4199, 2008.
Links: [doi:10.1021/Jm800054h] [show BibTeX]  x  @article{RN92, author = {Schuster, D. and Nashev, L. G. and Kirchmair, J. and Laggner, C. and Wolber, G. and Langer, T. and Odermatt, A.}, title = {Discovery of nonsteroidal 17 beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries}, journal = {Journal of Medicinal Chemistry}, volume = {51}, number = {14}, pages = {4188-4199}, ISSN = {0022-2623}, DOI = {Doi 10.1021/Jm800054h}, url = {Go to ISI://WOS:000257721600013 http://pubs.acs.org/doi/pdfplus/10.1021/jm800054h}, year = {2008}, abtract = {17 beta-Hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) plays a pivotal role in the local synthesis of the most potent estrogen estradiol. Its expression is a prognostic marker for the outcome of patients with breast cancer and inhibition of 17 beta-HSD I is currently under consideration for breast cancer prevention and treatment. We aimed to identify nonsteroidal 17 beta-HSD1 inhibitor scaffolds by virtual screening with pharmacophore models built from crystal structures containing steroidal compounds. The most promising model was validated by comparing predicted and experimentally determined inhibitory activities of several flavonoids. Subsequently, a virtual library of nonsteroidal compounds was screened against the 3D pharmacophore. Analysis of 14 selected compounds yielded four that inhibited the activity of human 17 beta-HSD1 (IC(50) below 50 mu M). Specificity assessment of identified 17 beta-HSD1 inhibitors emphasized the importance of including related short-chain dehydrogenase/reductase (SDR) members to analyze off-target effects. Compound 29 displayed at least 10-fold selectivity over the related SDR enzymes tested.}, type = {Journal Article}, keywords = {11-beta-hydroxysteroid dehydrogenase type-1 17-beta-hydroxy steroid dehydrogenase 3d qsar model breast-cancer potent inhibitors active-site prognostic-significance estradiol protein design} }

[22]

G. Wolber, T. Seidel, F. Bendix, and T. Langer. Molecule-pharmacophore superpositioning and pattern matching in computational drug design, Drug Discov Today, 13(1–2):23-29, 2008.
Links: [doi:10.1016/j.drudis.2007.09.007] [show BibTeX]  x  @article{RN190, author = {Wolber, Gerhard and Seidel, Thomas and Bendix, Fabian and Langer, Thierry}, title = {Molecule-pharmacophore superpositioning and pattern matching in computational drug design}, journal = {Drug Discovery Today}, volume = {13}, number = {1–2}, pages = {23-29}, ISSN = {1359-6446}, DOI = {10.1016/j.drudis.2007.09.007}, url = {http://www.sciencedirect.com/science/article/pii/S1359644607003996 https://pdf.sciencedirectassets.com/271275/1-s2.0-S1359644607X00230/1-s2.0-S1359644607003996/main.pdf?X-Amz-Security-Token= AgoJb3JpZ2luX2VjEJr%2F%2F%2F%2F%2F%2F%2F%2F%2F%2FwEaCXVzLWVhc3QtMSJHMEUCIBmGoQIBcjjZ5EaOK3PJ%2FGurZx%2F3iAg7AxgzJBGlS1pLAiEAqq3PoXrNmhK0J8VvhGKQxD8CDm2MMxpACdgEvvCDCF0q2gMIQhACGgwwNTkwMDM1NDY4NjUiDB%2FjPXYQeqnKPMIAZSq3Axc0m%2BRD9Wt3prnTKye3Cqvo0AREbqzZ946GaterseGXxpe%2BUb3tyOJVBoXAsvayOEvYdT75FjY53skFYyeai6OYOXjZRWTEelsGyFCQf8cT3DEzx4Q%2FSuFEL5blDoqhss6bszDRC5%2FuVVpSzUmF7%2BFyAgGxxPdatNCbBmiutHGyRMn4PicJgX1DP70wJovm2MIIfOQjtVBAoW1FPcQfo4A0fJI5ShSReUYAnaXr04R8cTE%2BTTnwOVhgNPw19doX3%2FZOAC3wHvx2xdw427PkU7STXll%2FivSFUP2UPMpj5wiro1CxQicswmv0RAWfVQV%2BoN9oIuCE4eWm%2FoT86KudK0SbLCkH8hiO85Gkxien8zQf3J%2BA2aXelkRNwjG55dMxfLKxuLd5mhDnokYj7cOpwsS9sVe2WOpNw0L83GU%2FpuvVJI9vZFARLk225K%2FQ4b1pFcwGOKOAZBiAQZJ9D7JWTWR0gA8Y9KTN%2FrSCDcM7e3OCrDWcifFbCTor1FSCUFanT4fycawD7p8nphvKBxLQcZTmUo0CLG0aAL6hXvuI45m7qu0ijPUXIyCJTvyurXi9RPRuVGihaxkw98KO6wU6tAGChddaHRM2ELzStD4I3%2BltvO8qU5OvXkFpFPXsJT4YQCQafydsDiutI4rsZ8MyFKk2VmqAYvFy3yg9tm4P88k25cm8YxrYD9FZBt34b46IAXloCTW%2BjWdZAQpgxFCuBBURFwPqw%2Bz5EL4gHYjp%2BQW%2FHnmtR8SfofKETRV74Znvs9OncFyjtB09l8I8dyXKRPvZSo%2BtyGyKRjRStMbqfOcty%2BjSd%2FWSyeoJFlE6ZwZclpM4vEI%3D&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20190826T090956Z&X-Amz-SignedHeaders=host&X-Amz-Expires=300&X-Amz-Credential=ASIAQ3PHCVTYQ4T4FY7Z%2F20190826%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Signature=2a92644509fcff0f30c4cecf224e5530afbd057c812b0037e6079eb945c5feaf&hash=942a02e541d3d7bdc91d26f8819910070b90cbdc3b8ab3e2f810af3a5c4c490e&host=68042c943591013ac2b2430a89b270f6af2c76d8dfd086a07176afe7c76c2c61&pii=S1359644607003996&tid=spdf-e78f20c4-403e-4aa3-86d9-9fe590eabea4&sid=2685c81b50af534a6f99d1c429305bd4118dgxrqb&type=client}, year = {2008}, abtract = {Three-dimensional (3D) pharmacophore modeling is a technique for describing the interaction of a small molecule ligand with a macromolecular target. Since chemical features in a pharmacophore model are well known and highly transparent for medicinal chemists, these models are intuitively understandable and have been increasingly successful in computational drug discovery in the past few years. The performance and applicability of pharmacophore modeling depends on two main factors: the definition and placement of pharmacophoric features and the alignment techniques used to overlay 3D pharmacophore models and small molecules. An overview of key technologies and latest developments in the area of 3D pharmacophores is given and provides insight into different approaches as implemented by the 3D pharmacophore modeling packages like Catalyst, MOE, Phase and LigandScout.}, type = {Journal Article}, }

[21]

J. Kirchmair, S. Ristic, K. Eder, P. Markt, G. Wolber, C. Laggner, and T. Langer. Fast and efficient in silico 3D screening: Toward maximum computational efficiency of pharmacophore-based and shape-based approaches, J Chem Inf Model, 47(6):2182-2196, 2007.
Links: [doi:10.1021/Ci700024q] [show BibTeX]  x  @article{RN100, author = {Kirchmair, J. and Ristic, S. and Eder, K. and Markt, P. and Wolber, G. and Laggner, C. and Langer, T.}, title = {Fast and efficient in silico 3D screening: Toward maximum computational efficiency of pharmacophore-based and shape-based approaches}, journal = {Journal of Chemical Information and Modeling}, volume = {47}, number = {6}, pages = {2182-2196}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci700024q}, url = {Go to ISI://WOS:000251216500016 http://pubs.acs.org/doi/pdfplus/10.1021/ci700024q}, year = {2007}, abtract = {In continuation of our recent studies on the quality of conformational models generated with CATALYST and OMEGA we present a large-scale survey focusing on the impact of conformational model quality and several screening parameters on pharmacophore-based and shape-based virtual high throughput screening (vHTS). Therefore, we collected known active compounds of CDK2, p38 MAPK, PPAR-gamma, and factor Xa and built a set of druglike decoys using ilib:diverse. Subsequently, we generated 3D structures using CORINA and also calculated conformational models for all compounds using CAESAR, CATALYST FAST, and OMEGA. A widespread set of 103 structure-based pharmacophore models was developed with LigandScout for virtual screening with CATALYST. The performance of both database search modes (FAST and BEST flexible database search) as well as the fit value calculation procedures (FAST and BEST fit) available in CATALYST were analyzed in terms of their ability to discriminate between active and inactive compounds and in terms of efficiency. Moreover, these results are put in direct comparison to the performance of the shape-based virtual screening platform ROCS. Our results prove that high enrichment rates are not necessarily in conflict with efficient vHTS settings: In most of the experiments, we obtained the highest yield of actives in the hit list when parameter sets for the fastest search algorithm were used.}, type = {Journal Article}, keywords = {protein-bound ligands conformational space inhibitors catalyst receptor binding design kinases models} }

[20]

J. Kirchmair, G. Wolber, C. Laggner, and T. Langer. Comparative performance assessment of the conformational model generators omega and catalyst: A large-scale survey on the retrieval of protein-bound ligand conformations, J Chem Inf Model, 46(4):1848-1861, 2006.
Links: [doi:10.1021/Ci060084g] [show BibTeX]  x  @article{RN111, author = {Kirchmair, J. and Wolber, G. and Laggner, C. and Langer, T.}, title = {Comparative performance assessment of the conformational model generators omega and catalyst: A large-scale survey on the retrieval of protein-bound ligand conformations}, journal = {Journal of Chemical Information and Modeling}, volume = {46}, number = {4}, pages = {1848-1861}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci060084g}, url = {Go to ISI://WOS:000239204400032 http://pubs.acs.org/doi/pdfplus/10.1021/ci060084g}, year = {2006}, abtract = {In continuation of our studies to evaluate the ability of various conformer generators to produce bioactive conformations, we present the extension of our work on the analysis of Catalyst's conformational subsampling algorithm in a comparative evaluation with OpenEye's currently updated tool Omega 2.0. Our study is based on an enhanced test set of 778 drug molecules and pharmacologically relevant compounds extracted from the Protein Data Bank (PDB). We elaborated protocols for two common conformer generation use cases and applied them to both programs: (i) high-throughput settings for processing large databases and (ii) high-quality settings for binding site exploration or lead structure refinement. While Catalyst is faster in the first case, Omega 2.0 better reproduces the bound ligand conformations from the PDB in less time for the latter case.}, type = {Journal Article}, keywords = {energy minimization coverage respect binding} }

[19]

T. M. Steindl, D. Schuster, G. Wolber, C. Laggner, and T. Langer. High-throughput structure-based pharmacophore modelling as a basis for successful parallel virtual screening, J Comput Aided Mol Des, 20(12):703-715, 2006.
Links: [doi:10.1007/S10822-006-9066-Y] [show BibTeX]  x  @article{RN107, author = {Steindl, T. M. and Schuster, D. and Wolber, G. and Laggner, C. and Langer, T.}, title = {High-throughput structure-based pharmacophore modelling as a basis for successful parallel virtual screening}, journal = {Journal of Computer-Aided Molecular Design}, volume = {20}, number = {12}, pages = {703-715}, ISSN = {0920-654X}, DOI = {Doi 10.1007/S10822-006-9066-Y}, url = {Go to ISI://WOS:000244093900001 http://download.springer.com/static/pdf/684/art%253A10.1007%252Fs10822-006-9066-y.pdf?auth66= 1411553713_72bc8c2cb9696a511117bc424b9e7d17&ext=.pdf}, year = {2006}, abtract = {In order to assess bioactivity profiles for small organic molecules we propose to use parallel pharmacophore-based virtual screening. Our aim is to provide a fast, reliable and scalable system that allows for rapid in silico activity profile prediction of virtual molecules. In this proof of principle study, carried out with the new structure-based pharmacophore modelling tool LigandScout and the high-performance database mining platform Catalyst, we present a model work for the application of parallel pharmacophore-based virtual screening on a set of 50 structure-based pharmacophore models built for various viral targets and 100 antiviral compounds. The latter were screened against all pharmacophore models in order to determine if their known biological targets could be correctly predicted via an enrichment of corresponding pharmacophores matching these ligands. The results demonstrate that the desired enrichment, i.e. a successful activity profiling, was achieved for approximately 90% of all input molecules. Additionally, we discuss descriptors for output validation, as well as various aspects influencing the analysis of the obtained activity profiles, and the effect of the searching mode utilized for screening. The results of the study presented here clearly indicate that pharmacophore-based parallel screening comprises a reliable in silico method to predict the potential biological activities of a compound or a compound library by screening it against a series of pharmacophore queries.}, type = {Journal Article}, keywords = {bioactivity profiling virtual screening pharmacophore modelling ligandscout structure-based pharmacophores database mining parallel screening bound ligand conformations inhibitors identification discovery design drugs} }

[18]

G. Wolber, A. A. Dornhofer, and T. Langer. Efficient overlay of small organic molecules using 3D pharmacophores, J Comput Aided Mol Des, 20(12):773-788, 2006.
Links: [doi:10.1007/S10822-006-9078-7] [show BibTeX]  x  @article{RN108, author = {Wolber, G. and Dornhofer, A. A. and Langer, T.}, title = {Efficient overlay of small organic molecules using 3D pharmacophores}, journal = {Journal of Computer-Aided Molecular Design}, volume = {20}, number = {12}, pages = {773-788}, ISSN = {0920-654X}, DOI = {Doi 10.1007/S10822-006-9078-7}, url = {Go to ISI://WOS:000244093900006 http://download.springer.com/static/pdf/37/art%253A10.1007%252Fs10822-006-9078-7.pdf?auth66= 1411553718_b433790d8568698a69115ed9e9065dde&ext=.pdf}, year = {2006}, abtract = {Aligning and overlaying two or more bio-active molecules is one of the key tasks in computational drug discovery and bio-activity prediction. Especially chemical-functional molecule characteristics from the view point of a macromolecular target represented as a 3D pharmacophore are the most interesting similarity measure when describing and analyzing macromolecule-ligand interaction. In this study, a novel approach for aligning rigid three-dimensional molecules according to their chemical-functional pharmacophoric features is presented and compared to the overlay of experimentally determined poses in a comparable macromolecule coordinate frame. The presented approach identifies optimal chemical feature pairs using distance and density characteristics obtained by correlating pharmacophoric geometries and thus proves to be faster than existing combinatorial alignment methods and creates more reasonable alignments than pure atom-based methods. Examples will be provided to demonstrate the feasibility, speed and intuitiveness of this method.}, type = {Journal Article}, keywords = {molecular alignment molecular superimposition pharmacophore ligandscout relate 2 sets rotation vectors} }

[17]

J. Kirchmair, C. Laggner, G. Wolber, and T. Langer. Comparative analysis of protein-bound ligand conformations with respect to catalyst's conformational space subsampling algorithms, J Chem Inf Model, 45(2):422-430, 2005.
Links: [doi:10.1021/Ci0497531] [show BibTeX]  x  @article{RN116, author = {Kirchmair, J. and Laggner, C. and Wolber, G. and Langer, T.}, title = {Comparative analysis of protein-bound ligand conformations with respect to catalyst's conformational space subsampling algorithms}, journal = {Journal of Chemical Information and Modeling}, volume = {45}, number = {2}, pages = {422-430}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci0497531}, url = {Go to ISI://WOS:000228018000028 http://pubs.acs.org/doi/pdfplus/10.1021/ci049753l}, year = {2005}, abtract = {We examined the quality of Catalyst's conformational model generation algorithm via a large scale study based on the crystal structures of a sample of 510 pharmaceutically relevant protein-ligand complexes extracted from the Protein Data Bank (PDB). Our results show that the tested algorithms implemented within Catalyst are able to produce high quality conformers, which in most of the cases are well suited for in silico drug research. Catalyst-specific settings were analyzed, such as the method used for the conformational model generation (FAST vs BEST) and the maximum number of generated conformers. By setting these options for higher fitting quality, the average RMS values describing the similarity of experimental and simulated conformers were improved from an RMS of 1.06 with max. 50 FAST generated conformers to an RMS of 0.93 with max. 255 BEST generated conformers, which represents an improvement by 12%. Each method provides best fitting conformers with an RMS value 1.50 in more than 80% of all cases. We analyzed the computing time/quality ratio of various conformational model generation settings and examined ligands in high energy conformations. Furthermore, properties of the same ligands in various proteins were investigated, and the fitting qualities of experimental conformations from the PDB and the Cambridge Structural Database (CSD) were compared. One of the most important conclusions of former studies, the fact that bioactive conformers often have energy high above that of Global minima, was confirmed.}, type = {Journal Article}, keywords = {enzyme action active-site coverage binding} }

[16]

G. Wolber, and T. Langer. LigandScout: 3-d pharmacophores derived from protein-bound Ligands and their use as virtual screening filters, J Chem Inf Model, 45(1):160-169, 2005.
Links: [doi:10.1021/Ci049885e] [show BibTeX]  x  @article{RN117, author = {Wolber, G. and Langer, T.}, title = {LigandScout: 3-d pharmacophores derived from protein-bound Ligands and their use as virtual screening filters}, journal = {Journal of Chemical Information and Modeling}, volume = {45}, number = {1}, pages = {160-169}, ISSN = {1549-9596}, DOI = {Doi 10.1021/Ci049885e}, url = {Go to ISI://WOS:000227982800019 http://pubs.acs.org/doi/pdfplus/10.1021/ci049885e}, year = {2005}, abtract = {From the historically grown archive of protein-ligand complexes in the Protein Data Bank small organic ligands are extracted and interpreted in terms of their chemical characteristics and features. Subsequently, pharmacophores representing ligand-receptor interaction are derived from each of these small molecules and its surrounding amino acids. Based on a defined set of only six types of chemical features and volume constraints, three-dimensional pharmacophore models are constructed, which are sufficiently selective to identify the described binding mode and are thus a useful tool for in-silico screening of large compound databases. The algorithms for ligand extraction and interpretation as well as the pharmacophore creation technique from the automatically interpreted data are presented and applied to a rhinovirus capsid complex as application example.}, type = {Journal Article}, keywords = {software} }

[15]

T. Langer, and G. Wolber. Pharmacophore definition and 3D searches, Drug Discovery Today: Technologies, 1(3):203-207, 2004.
Links: [doi:10.1016/j.ddtec.2004.11.015] [show BibTeX]  x  @article{RN150, author = {Langer, T. and Wolber, G.}, title = {Pharmacophore definition and 3D searches}, journal = {Drug Discovery Today: Technologies}, volume = {1}, number = {3}, pages = {203-207}, ISSN = {1740-6749}, DOI = {10.1016/j.ddtec.2004.11.015}, url = {http://www.sciencedirect.com/science/article/pii/S1740674904000630 http://ac.els-cdn.com/S1740674904000630/1-s2.0-S1740674904000630-main.pdf?_tid= a8039fb2-4338-11e4-978e-00000aab0f02&acdnat=1411487314_713ac491b1ee97828269b62f0b50e6b6}, year = {2004}, abtract = {The most common pharmacophore building concepts based on either 3D structure of the target or ligand information are discussed together with the application of such models as queries for 3D database search. An overview of the key techniques available on the market is given and differences with respect to algorithms used and performance obtained are highlighted. Pharmacophore modelling and 3D database search are shown to be successful tools for enriching screening experiments aimed at the discovery of novel bio-active compounds. Section Editor: Hugo Kubiniyi – University of Heidelberg, Germany Pharmacophore models are hypotheses on the 3D arrangement of structural properties, such as hydrogen bond donar and acceptor properties, hydrophobic groups and aromatic rings of compounds that bind to a biological target. In the presence of the 3D structure of this target of by comparison with inactive analogs, further geometric and/or steric constraints can be defined. The article describes and evaluates strategies and commercial software for pharmacophore definition, starting from the 3D structures of ligand-protein complexes or from ligands alone. Once a pharmacophore model is established, 3D searches in large databases can be performed, leading to a significant enrichment of active analogs.}, type = {Journal Article}, }

[14]

T. Langer, and G. Wolber. Virtual combinatorial chemistry and in silico screening: Efficient tools for lead structure discovery?, Pure Appl Chem, 76(5):991-996, 2004.
Links: [doi:10.1351/Pac200476050991] [show BibTeX]  x  @article{RN118, author = {Langer, T. and Wolber, G.}, title = {Virtual combinatorial chemistry and in silico screening: Efficient tools for lead structure discovery?}, journal = {Pure and Applied Chemistry}, volume = {76}, number = {5}, pages = {991-996}, ISSN = {0033-4545}, DOI = {Doi 10.1351/Pac200476050991}, url = {Go to ISI://WOS:000222693700012 http://www.degruyter.com/view/j/pac.2004.76.issue-5/pac200476050991/pac200476050991.xml http://www.degruyter.com/dg/viewarticle.fullcontentlink:pdfeventlink/$002fj$002fpac.2004.76.issue-5$002fpac200476050991$002fpac200476050991.pdf?t:ac= j$002fpac.2004.76.issue-5$002fpac200476050991$002fpac200476050991.xml}, year = {2004}, abtract = {In this article, an overview of the most common ligand-based in silico screening techniques is given together with an example on the recent successful application of combined use of pharmacophore modeling, database mining, and biological assays. Additionally, a new approach for structure-based high-throughput pharmacophore model generation is presented. The LigandScout program contains an automated method for creating pharmacophore models from experimentally determined structure data, e.g., publicly available from the Brookhaven Protein Databank (PDB). In a first step, known algorithms were implemented and improved to extract small-molecule ligands from the PDB including assignment of hybridization states and bond orders. Second, from the interactions of the interpreted ligands with relevant surrounding amino acids, pharmacophore models reflecting functional interactions like H-bonds or ionic transfer interactions were created. These models can be used for screening molecular databases for similar modes of actions on the one hand, or for screening one single compound for potential side-effects (reversed screening) on the other hand. The implementation was done using the ilib framework, which also formed the basis of the software tool Comb(i)Gen, a fragment-based virtual combinatorial library generation program enabling the user to obtain in silico compound collections with high drug-likeness.}, type = {Journal Article}, keywords = {natural-products drug design library} }

Book chapters

D. Schuster and G. Wolber. Addressing drug safety by bioactivity profiling: panels of 3D pharmacophore models, In: Adverse side effect prediction in preclinical drug discovery, J. Scheiber and J. Jenkins, editors, Wiley VCH, Weinheim, Germany, in print, 2019. [show BibTeX]  x  @inbook{RN143, author = {Schuster, D. and Wolber, G.}, title = {Addressing drug safety by bioactivity profiling: panels of 3D pharmacophore models}, booktitle = {Adverse side effect prediction in preclinical drug discovery}, editor = {Scheiber, J. and Jenkins, J.}, publisher = {Wiley VCH}, address = {Weinheim, Germany}, pages = {in print}, year = {2019}, type = {Book Section} }

T. Seidel, G. Wolber and M. S. Murgueitio. Pharmacophore Perception and Applications, In: Applied Chemoinformatics: Achievements and Future Opportunities, J. Gasteiger and T. Engel, editors, , pp. 259-282, 2018. [show BibTeX]  x  @inbook{RN195, author = {Seidel, Thomas and Wolber, Gerhard and Murgueitio, Manuela S.}, title = {Pharmacophore Perception and Applications}, booktitle = {Applied Chemoinformatics: Achievements and Future Opportunities}, editor = {Gasteiger, Johann and Engel, Thomas}, pages = {259-282}, year = {2018}, type = {Book Section} }

D. Schuster, J. Kirchmair, S. Distinto, P. Markt, C. Laggner, G. Wolber and T. Langer. Why drugs and advanced drug development projects fail, In: Why Drugs Fail, T. Langer and S. D. Bryant, editors, Wiley VCH, Weinheim, Germany, in print, 2017. [show BibTeX]  x  @inbook{RN142, author = {Schuster, D. and Kirchmair, J. and Distinto, S. and Markt, P. and Laggner, C. and Wolber, G. and Langer, T.}, title = {Why drugs and advanced drug development projects fail}, booktitle = {Why Drugs Fail}, editor = {Langer, T. and Bryant, S. D.}, publisher = {Wiley VCH}, address = {Weinheim, Germany}, pages = {in print}, year = {2017}, type = {Book Section} }

G. Wolber and W. Sippl. Pharmacophore Identification and Pseudo-Receptor Modelling, In: The Practice of Medicinal Chemistry (4th edition), C. G. Wermuth and D. Rognan, editors, Elsevier Ltd, Philadelphia, PA, USA, pp. 489-507, 2015.
Links: [Publisher] [show BibTeX]  x  @inbook{RN144, author = {Wolber, G. and Sippl, W.}, title = {Pharmacophore Identification and Pseudo-Receptor Modelling}, booktitle = {The Practice of Medicinal Chemistry (4th edition)}, editor = {Wermuth, C. G. and Rognan, D.}, publisher = {Elsevier Ltd}, address = {Philadelphia, PA, USA}, pages = {489-507}, url = {https://www.elsevier.com/books/the-practice-of-medicinal-chemistry/wermuth/978-0-12-417205-0}, year = {2015}, type = {Book Section} }

G. Wolber and J. Rollinger. Virtual screening and target fishing for natural products using 3D pharmacophores, In: Computational Chemogenomics, E. Jacoby, editor, Pan Stanford Publishing Pte Ltd, Singapore, Malaysia, ISBN: 978-981-4411-39-4, pp. 117-139, 2013.
Links: [Publisher] [show BibTeX]  x  @inbook{RN141, author = {Wolber, G. and Rollinger, J.M.}, title = {Virtual screening and target fishing for natural products using 3D pharmacophores}, booktitle = {Computational Chemogenomics}, editor = {Jacoby, E.}, publisher = {Pan Stanford Publishing Pte Ltd}, address = {Singapore, Malaysia}, pages = {117-139}, ISBN = {978-981-4411-39-4}, DOI = {10.1201/b15631}, url = {http://www.crcnetbase.com/doi/book/10.1201/b15631}, year = {2013}, type = {Book Section} }

J. M. Rollinger and G. Wolber. Computational approaches for the discovery of natural lead structures, In: Bioactive Compounds from Natural Sources, 2nd edition, C. Tringali, editor, CRC Press, London, United Kingdom, ISBN: 1439822298, pp. 97-132, 2011.
Links: [Publisher] [show BibTeX]  x  @inbook{RN140, author = {Rollinger, J. M. and Wolber, G.}, title = {Computational approaches for the discovery of natural lead structures}, booktitle = {Bioactive Compounds from Natural Sources, 2nd edition}, editor = {Tringali, C. }, publisher = {CRC Press}, address = {London, United Kingdom}, pages = {97-132}, ISBN = {1439822298}, DOI = {10.1201/b11196}, url = {http://www.crcnetbase.com/doi/book/10.1201/b11196}, year = {2011}, type = {Book Section} }

C. Laggner, G. Wolber, J. Kirchmair, S. D. and L. T.. Pharmacophore-based virtual screening in drug discovery, In: Chemoinformatics: An approach to virtual screening, A. Varnek and A. Tropsha, editors, Royal Society of Chemistry, Cambridge, United Kingdom, ISBN: 978-0-85404-144-2, pp. 76-119, 2008.
Links: [Publisher] [show BibTeX]  x  @inbook{RN139, author = {Laggner, C. and Wolber, G. and Kirchmair, J. and Schuster D. and T., Langer}, title = {Pharmacophore-based virtual screening in drug discovery}, booktitle = {Chemoinformatics: An approach to virtual screening}, editor = {Varnek, A. and Tropsha, A.}, publisher = {Royal Society of Chemistry}, address = {Cambridge, United Kingdom}, pages = {76-119}, ISBN = {978-0-85404-144-2}, DOI = {10.1039/9781847558879}, url = {http://pubs.rsc.org/en/Content/eBook/978-0-85404-144-2#!divbookcontent}, year = {2008}, type = {Book Section} }

A. A. Dornhofer, M. Biely, G. Wolber and T. Langer. A novel 2D depiction method using breadth-first ordering and an adapted 2D force field, In: QSAR and Molecular Modelling in Rational Design of Bioactive Molecules, E. Aki Sener and I. Yalcin, editors, Computer Aided Drug Design & Development Society, Ankara, Turkey, ISBN: 975-00782-0-9, pp. 421ff., 2006. [show BibTeX]  x  @inbook{RN135, author = {Dornhofer, A. A. and Biely, M. and Wolber, G. and Langer, T.}, title = {A novel 2D depiction method using breadth-first ordering and an adapted 2D force field}, booktitle = {QSAR and Molecular Modelling in Rational Design of Bioactive Molecules}, editor = {Aki Sener, E. and Yalcin, I.}, publisher = {Computer Aided Drug Design & Development Society}, address = {Ankara, Turkey}, pages = {421ff.}, ISBN = {975-00782-0-9}, year = {2006}, type = {Book Section} }

T. Langer and G. Wolber. Extracting pharmacophores from bio-active molecules, In: Virtual ADMET assessment in target Selection and maturation, B. Testa and L. Turski, editors, IOS Press, Amsterdam, Netherlands, ISBN: 978-1-58603-703-1, pp. 133-150, 2006. [show BibTeX]  x  @inbook{RN153, author = {Langer, T. and Wolber, G.}, title = {Extracting pharmacophores from bio-active molecules}, booktitle = {Virtual ADMET assessment in target Selection and maturation}, editor = {Testa, B. and Turski, L.}, series = { Solvay pharmaceutical conferences}, publisher = {IOS Press, Amsterdam, Netherlands}, pages = {133-150}, ISBN = {978-1-58603-703-1}, year = {2006}, type = {Book Section} }

G. Wolber, M. Biely and T. Langer. De novo drug design using randomized virtual chemistry and property filtering: a heuristic approach, In: QSAR and Molecular Modelling in Rational Design of Bioactive Molecules, E. Aki Sener and I. Yalcin, editors, Computer Aided Drug Design & Development Society, Ankara, Turkey, ISBN: 975-00782-0-9, pp. , 2006. [show BibTeX]  x  @inbook{RN136, author = {Wolber, Gerhard and Biely, Martin and Langer, Thierry}, title = {De novo drug design using randomized virtual chemistry and property filtering: a heuristic approach}, booktitle = {QSAR and Molecular Modelling in Rational Design of Bioactive Molecules}, editor = {Aki Sener, E. and Yalcin, I.}, publisher = {Computer Aided Drug Design & Development Society}, address = {Ankara, Turkey}, ISBN = {975-00782-0-9}, year = {2006}, type = {Book Section} }

G. Wolber and R. Kosara. Pharmacophores from macromolecular complexes with LigandScout, In: Pharmacophores and pharmacophore searches, T. Langer and R. Hofmann, editors, Wiley-VCH, Weinheim, Germany, ISBN: 3-527-31250-1, pp. 131-148, 2006.
Links: [Publisher] [show BibTeX]  x  @inbook{RN138, author = {Wolber, G. and Kosara, R.}, title = {Pharmacophores from macromolecular complexes with LigandScout}, booktitle = {Pharmacophores and pharmacophore searches}, editor = {Langer, T. and Hofmann, R.}, publisher = {Wiley-VCH}, address = {Weinheim, Germany}, volume = {32}, pages = {131-148}, ISBN = {3-527-31250-1}, url = {http://eu.wiley.com/WileyCDA/WileyTitle/productCd-3527608729.html}, year = {2006}, type = {Book Section} }

G. Wolber. Structure-based Pharmacophores From Protein-Bound Ligands (German: Strukturbasierte Pharmacophore aus proteingebundenen Liganden), In: Lecture notes in informatics (LNI) D-5, D. Wagner, editor, Bonner Koellen Verlag, Bonn-Buschdorf, Germany, ISBN: 3-88579-409-8, pp. 209-218, 2004. [show BibTeX]  x  @inbook{RN134, author = {Wolber, G.}, title = {Structure-based Pharmacophores From Protein-Bound Ligands (German: Strukturbasierte Pharmacophore aus proteingebundenen Liganden)}, booktitle = {Lecture notes in informatics (LNI) D-5}, editor = {Wagner, D. }, publisher = {Bonner Koellen Verlag}, address = {Bonn-Buschdorf, Germany}, pages = {209-218}, ISBN = {3-88579-409-8}, year = {2004}, type = {Book Section} }

T. Langer and G. Wolber. CombiGen: A Novel Software Package for the Rapid Generation of Virtual Combinatorial Libraries, In: Rational Approaches to Drug Design, W. Höltje, editor, Prous Science, Barcelona, Spain, ISBN: 84-8124-176-8, pp. 390-399, 2001. [show BibTeX]  x  @inbook{RN133, author = {Langer, Thierry and Wolber, Gerhard}, title = {CombiGen: A Novel Software Package for the Rapid Generation of Virtual Combinatorial Libraries}, booktitle = {Rational Approaches to Drug Design}, editor = {Höltje, H.-D; Sippl, W.}, publisher = {Prous Science}, address = {Barcelona, Spain}, pages = {390-399}, ISBN = { 84-8124-176-8}, year = {2001}, type = {Book Section} }

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