Discovery of a Non-Peptidic Inhibitor of West Nile Virus NS3 Protease by High-Throughput Docking

被引：60

作者：

Ekonomiuk, Dariusz ^{[1
]}

Su, Xun-Cheng ^{[2
]}

Ozawa, Kiyoshi ^{[2
]}

Bodenreider, Christophe ^{[3
]}

Lim, Siew Pheng ^{[3
]}

Yin, Zheng ^{[3
]}

Keller, Thomas H. ^{[3
]}

Beer, David ^{[3
]}

Patel, Viral ^{[3
]}

Otting, Gottfried ^{[2
]}

Caflisch, Amedeo ^{[1
]}

Huang, Danzhi ^{[1
]}

机构：

[1] Univ Zurich, Dept Biochem, Zurich, Switzerland

[2] Australian Natl Univ, Res Sch Chem, Canberra, ACT, Australia

[3] Novartis Inst Trop Dis, Chromos, Singapore

来源：

PLOS NEGLECTED TROPICAL DISEASES | 2009年 / 3卷 / 01期

关键词：

HEPATITIS-C-VIRUS; ORBITAL ELECTRONEGATIVITY METHOD; MODIFIED PARTIAL EQUALIZATION; SERINE-PROTEASE; ANTIVIRAL ACTIVITY; PEPTIDE INHIBITORS; INTERACTION ENERGIES; BETA-SECRETASE; BINDING; POTENT;

D O I：

10.1371/journal.pntd.0000356

中图分类号：

R51 [传染病];

学科分类号：

100401 ;

摘要：

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 N-15-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.

引用

页数：9

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