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Discovery of a non-peptidic inhibitor of West Nile virus NS3 protease by high-throughput docking

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dc.contributor.authorEkonomiuk, Dariusz
dc.contributor.authorSu, Xun-Cheng
dc.contributor.authorOzawa, Kiyoshi
dc.contributor.authorBodenreider, Christophe
dc.contributor.authorLim, Siew P
dc.contributor.authorYin, Zheng
dc.contributor.authorKeller, Thomas H
dc.contributor.authorBeer, David
dc.contributor.authorPatel, Viral
dc.contributor.authorCaflisch, Amedeo
dc.contributor.authorHuang, Danzhi
dc.contributor.authorOtting, Gottfried
dc.date.accessioned2009-06-16T05:46:41Zen_US
dc.date.accessioned2010-12-20T06:05:59Z
dc.date.available2009-06-16T05:46:41Zen_US
dc.date.available2010-12-20T06:05:59Z
dc.date.issued2009-01-13en_US
dc.date.updated2016-02-24T10:22:55Z
dc.description.abstractBACKGROUND: 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.
dc.format9 pages
dc.identifier.citationPLoS Neglected Tropical Diseases 3.1 (2009): e356
dc.identifier.issn1935-2735en_US
dc.identifier.issn1935-2727en_US
dc.identifier.urihttp://hdl.handle.net/10440/487en_US
dc.identifier.urihttp://digitalcollections.anu.edu.au/handle/10440/487
dc.publisherPublic Library of Science
dc.rightsThis 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 work is properly cited.
dc.sourcePLoS Neglected Tropical Diseases
dc.source.urihttp://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000356en_US
dc.subjectKeywords: [4 (carbamimidoylsulfanylmethyl) 2,5 dimethylphenyl]methylsulfanylmethanimidamide; amide; hydrogen; nonstructural protein 3; proteinase; proteinase inhibitor; tryptophan; unclassified drug; (4 (carbamimidoylsulfanylmethyl) 2,5 dimethylphenyl)methylsulfany
dc.titleDiscovery of a non-peptidic inhibitor of West Nile virus NS3 protease by high-throughput docking
dc.typeJournal article
dcterms.dateAccepted2008-12-14en_US
local.bibliographicCitation.issue1
local.bibliographicCitation.lastpage9
local.bibliographicCitation.startpagee356/1
local.contributor.affiliationEkonomiuk, Dariusz, University of Zurichen_US
local.contributor.affiliationSu, Xun-Cheng, Research School of Chemistryen_US
local.contributor.affiliationOzawa, Kiyoshi, Research School of Chemistryen_US
local.contributor.affiliationBodenreider, Christophe, Novartis Institute for Tropical Diseases Pty Ltd, Singaporeen_US
local.contributor.affiliationLim, Siew P, Novartis Institute for Tropical Diseases Pty Ltd, Singaporeen_US
local.contributor.affiliationYin, Zheng, Novartis Institute for Tropical Diseases Pty Ltd, Singaporeen_US
local.contributor.affiliationKeller, Thomas H, Novartis Institute for Tropical Diseases Pty Ltd, Singaporeen_US
local.contributor.affiliationBeer, David, Novartis Institute for Tropical Diseases Pty Ltd, Singaporeen_US
local.contributor.affiliationPatel, Viral, Novartis Institute for Tropical Diseases Pty Ltd, Singaporeen_US
local.contributor.affiliationOtting, Gottfried, Research School of Chemistryen_US
local.contributor.affiliationCaflisch, Amedeo, University of Zurichen_US
local.contributor.affiliationHuang, Danzhi, University of Zurichen_US
local.contributor.authoruidE33203en_US
local.contributor.authoruidu4175170en_US
local.contributor.authoruidu4050581en_US
local.contributor.authoruidE33205en_US
local.contributor.authoruidE23571en_US
local.contributor.authoruidE33206en_US
local.contributor.authoruidE33211en_US
local.contributor.authoruidE33207en_US
local.contributor.authoruidE33208en_US
local.contributor.authoruidu4046684en_US
local.contributor.authoruidE33209en_US
local.contributor.authoruidE33210en_US
local.identifier.absfor060107en_US
local.identifier.ariespublicationu4005981xPUB301en_US
local.identifier.citationvolume3
local.identifier.doi10.1371/journal.pntd.0000356
local.identifier.scopusID2-s2.0-65549122954
local.identifier.thomsonID000263301100005
local.type.statusPublished Versionen_US

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