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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-17806

Ekonomiuk, D; Su, X-C; Ozawa, K; Bodenreider, C; Lim, S P; Yin, Z; Keller, T H; Beer, D; Patel, V; Otting, G; Caflisch, A; Huang, D (2009). Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking. PLoS Neglected Tropical Diseases, 3(1):e356.

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Abstract

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.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Biochemistry
07 Faculty of Science > Institute of Biochemistry
DDC:570 Life sciences; biology
Language:English
Date:13 January 2009
Deposited On:16 Mar 2009 16:42
Last Modified:28 Nov 2013 10:43
Publisher:Public Library of Science
ISSN:1935-2727
Publisher DOI:10.1371/journal.pntd.0000356
PubMed ID:19159012
Citations:Web of Science®. Times Cited: 39
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