Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking.
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.


METHODS
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.


CONCLUSIONS
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.
Ekonomiuk
Dariusz
D
Department of Biochemistry, University of Zürich, Zürich, Switzerland.
Su
Xun-Cheng
XC
Ozawa
Kiyoshi
K
Bodenreider
Christophe
C
Lim
Siew Pheng
SP
Yin
Zheng
Z
Keller
Thomas H
TH
Beer
David
D
Patel
Viral
V
Otting
Gottfried
G
Caflisch
Amedeo
A
Huang
Danzhi
D
D000998:Antiviral Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D057057:Serine Proteases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014902:West Nile virus / Q000201:enzymology*
C547922:(4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl)methylsulfanylmethanimidamide; D000998:Antiviral Agents; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D057057:Serine Proteases; D013890:Thiourea