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

doi:10.1371/journal.pntd.0000356

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

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.

Original language	English
Article number	e356
Journal	PLoS Neglected Tropical Diseases
Volume	3
Issue number	1
DOIs	https://doi.org/10.1371/journal.pntd.0000356
Publication status	Published - 2009

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

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.",

author = "Dariusz Ekonomiuk and Su, {Xun Cheng} and Kiyoshi Ozawa and Christophe Bodenreider and Lim, {Siew Pheng} and Zheng Yin and Keller, {Thomas H.} and David Beer and Viral Patel and Gottfried Otting and Amedeo Caflisch and Danzhi Huang",

year = "2009",

doi = "10.1371/journal.pntd.0000356",

language = "English",

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journal = "PLoS Neglected Tropical Diseases",

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AU - Ekonomiuk, Dariusz

AU - Su, Xun Cheng

AU - Ozawa, Kiyoshi

AU - Bodenreider, Christophe

AU - Lim, Siew Pheng

AU - Yin, Zheng

AU - Keller, Thomas H.

AU - Beer, David

AU - Patel, Viral

AU - Otting, Gottfried

AU - Caflisch, Amedeo

AU - Huang, Danzhi

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

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

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