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Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking
BACKGROUND: The non-structural 3 protease (NS3pro) is an essential flaviviral enzyme and therefore one of the most promising targets for drug development against West Nile virus (WNV) and dengue infections. METHODOLOGY: In this work, a small-molecule inhibitor of the WNV NS3pro has been identified b...
Autores principales: | , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613028/ https://www.ncbi.nlm.nih.gov/pubmed/19159012 http://dx.doi.org/10.1371/journal.pntd.0000356 |
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author | Ekonomiuk, Dariusz Su, Xun-Cheng Ozawa, Kiyoshi Bodenreider, Christophe Lim, Siew Pheng Yin, Zheng Keller, Thomas H. Beer, David Patel, Viral Otting, Gottfried Caflisch, Amedeo Huang, Danzhi |
author_facet | Ekonomiuk, Dariusz Su, Xun-Cheng Ozawa, Kiyoshi Bodenreider, Christophe Lim, Siew Pheng Yin, Zheng Keller, Thomas H. Beer, David Patel, Viral Otting, Gottfried Caflisch, Amedeo Huang, Danzhi |
author_sort | Ekonomiuk, Dariusz |
collection | PubMed |
description | BACKGROUND: The non-structural 3 protease (NS3pro) is an essential flaviviral enzyme and therefore one of the most promising targets for drug development against West Nile virus (WNV) and dengue infections. METHODOLOGY: In this work, a small-molecule inhibitor of the WNV NS3pro has been identified by automatic fragment-based docking of about 12000 compounds and testing by nuclear magnetic resonance (NMR) spectroscopy of only 22 molecules. Specific binding of the inhibitor into the active site of NS3pro and its binding mode are confirmed by (15)N-HSQC NMR spectra. The inhibitory activity is further validated by an enzymatic assay and a tryptophan fluorescence quenching assay. CONCLUSION: The inhibitor [4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl]-methylsulfanylmethanimidamide has a good ratio of binding affinity versus molecular weight (ligand efficiency of 0.33 kcal/mol per non-hydrogen atom), and thus has good potential as lead compound for further development to combat West Nile virus infections. |
format | Text |
id | pubmed-2613028 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-26130282009-01-13 Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking Ekonomiuk, Dariusz Su, Xun-Cheng Ozawa, Kiyoshi Bodenreider, Christophe Lim, Siew Pheng Yin, Zheng Keller, Thomas H. Beer, David Patel, Viral Otting, Gottfried Caflisch, Amedeo Huang, Danzhi PLoS Negl Trop Dis Research Article BACKGROUND: The non-structural 3 protease (NS3pro) is an essential flaviviral enzyme and therefore one of the most promising targets for drug development against West Nile virus (WNV) and dengue infections. METHODOLOGY: In this work, a small-molecule inhibitor of the WNV NS3pro has been identified by automatic fragment-based docking of about 12000 compounds and testing by nuclear magnetic resonance (NMR) spectroscopy of only 22 molecules. Specific binding of the inhibitor into the active site of NS3pro and its binding mode are confirmed by (15)N-HSQC NMR spectra. The inhibitory activity is further validated by an enzymatic assay and a tryptophan fluorescence quenching assay. CONCLUSION: The inhibitor [4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl]-methylsulfanylmethanimidamide has a good ratio of binding affinity versus molecular weight (ligand efficiency of 0.33 kcal/mol per non-hydrogen atom), and thus has good potential as lead compound for further development to combat West Nile virus infections. Public Library of Science 2009-01-13 /pmc/articles/PMC2613028/ /pubmed/19159012 http://dx.doi.org/10.1371/journal.pntd.0000356 Text en Ekonomiuk et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Ekonomiuk, Dariusz Su, Xun-Cheng Ozawa, Kiyoshi Bodenreider, Christophe Lim, Siew Pheng Yin, Zheng Keller, Thomas H. Beer, David Patel, Viral Otting, Gottfried Caflisch, Amedeo Huang, Danzhi Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking |
title | Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking |
title_full | Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking |
title_fullStr | Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking |
title_full_unstemmed | Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking |
title_short | Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking |
title_sort | discovery of a non-peptidic inhibitor of west nile virus ns3 protease by high-throughput docking |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613028/ https://www.ncbi.nlm.nih.gov/pubmed/19159012 http://dx.doi.org/10.1371/journal.pntd.0000356 |
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