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.
  
  
  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.
authors.affiliation: Department of Biochemistry, University of Zürich, Zürich, Switzerland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Ekonomiuk
authors.forename: Xun-Cheng
authors.initials: XC
authors.lastname: Su
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ozawa
authors.forename: Christophe
authors.initials: C
authors.lastname: Bodenreider
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Lim
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.forename: Viral
authors.initials: V
authors.lastname: Patel
authors.forename: Gottfried
authors.initials: G
authors.lastname: Otting
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
authors.forename: Danzhi
authors.initials: D
authors.lastname: Huang
mesh_terms: 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*
chemical_list: C547922:(4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl)methylsulfanylmethanimidamide; D000998:Antiviral Agents; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D057057:Serine Proteases; D013890:Thiourea