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...
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ftdoajarticles:oai:doaj.org/article:d97a5dd5a6634165b127e4c93e17b4e7 2023-05-15T15:04:19+02:00 Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking. Dariusz Ekonomiuk Xun-Cheng Su Kiyoshi Ozawa Christophe Bodenreider Siew Pheng Lim Zheng Yin Thomas H Keller David Beer Viral Patel Gottfried Otting Amedeo Caflisch Danzhi Huang 2009-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0000356 https://doaj.org/article/d97a5dd5a6634165b127e4c93e17b4e7 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2613028?pdf=render https://doaj.org/toc/1935-2735 1935-2735 doi:10.1371/journal.pntd.0000356 https://doaj.org/article/d97a5dd5a6634165b127e4c93e17b4e7 PLoS Neglected Tropical Diseases, Vol 3, Iss 1, p e356 (2009) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2009 ftdoajarticles https://doi.org/10.1371/journal.pntd.0000356 2022-12-30T23:55:18Z 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 15N-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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 3 1 e356 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Dariusz Ekonomiuk Xun-Cheng Su Kiyoshi Ozawa Christophe Bodenreider Siew Pheng Lim Zheng Yin Thomas H Keller David Beer Viral Patel Gottfried Otting Amedeo Caflisch Danzhi Huang Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 15N-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 |
Article in Journal/Newspaper |
author |
Dariusz Ekonomiuk Xun-Cheng Su Kiyoshi Ozawa Christophe Bodenreider Siew Pheng Lim Zheng Yin Thomas H Keller David Beer Viral Patel Gottfried Otting Amedeo Caflisch Danzhi Huang |
author_facet |
Dariusz Ekonomiuk Xun-Cheng Su Kiyoshi Ozawa Christophe Bodenreider Siew Pheng Lim Zheng Yin Thomas H Keller David Beer Viral Patel Gottfried Otting Amedeo Caflisch Danzhi Huang |
author_sort |
Dariusz Ekonomiuk |
title |
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_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_sort |
discovery of a non-peptidic inhibitor of west nile virus ns3 protease by high-throughput docking. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2009 |
url |
https://doi.org/10.1371/journal.pntd.0000356 https://doaj.org/article/d97a5dd5a6634165b127e4c93e17b4e7 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 3, Iss 1, p e356 (2009) |
op_relation |
http://europepmc.org/articles/PMC2613028?pdf=render https://doaj.org/toc/1935-2735 1935-2735 doi:10.1371/journal.pntd.0000356 https://doaj.org/article/d97a5dd5a6634165b127e4c93e17b4e7 |
op_doi |
https://doi.org/10.1371/journal.pntd.0000356 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
3 |
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1 |
container_start_page |
e356 |
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1766336105025634304 |