Discovery of a non-peptidic inhibitor of West Nile virus NS3 protease by high-throughput docking
Date
2009-01-13
Authors
Ekonomiuk, Dariusz
Su, Xun-Cheng
Ozawa, Kiyoshi
Bodenreider, Christophe
Lim, Siew P
Yin, Zheng
Keller, Thomas H
Beer, David
Patel, Viral
Caflisch, Amedeo
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
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 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.
Description
Keywords
Keywords: [4 (carbamimidoylsulfanylmethyl) 2,5 dimethylphenyl]methylsulfanylmethanimidamide; amide; hydrogen; nonstructural protein 3; proteinase; proteinase inhibitor; tryptophan; unclassified drug; (4 (carbamimidoylsulfanylmethyl) 2,5 dimethylphenyl)methylsulfany
Citation
PLoS Neglected Tropical Diseases 3.1 (2009): e356
Collections
Source
PLoS Neglected Tropical Diseases
Type
Journal article
Book Title
Entity type
Access Statement
License Rights
Restricted until
Downloads
File
Description