Abstract
BackgroundThe 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.MethodologyIn 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.ConclusionThe 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.
Highlights
West Nile virus (WNV) and the closely related dengue virus, members of the family Flaviviridae, are worldwide-spread global threats transmitted by mosquito bites
The non-structural 3 protease (NS3pro) is one of the most promising targets for drug development against flaviviridae infections because it is responsible for cleavage of the viral polyprotein precursor and plays a pivotal role in viral replication [3,4]
Only a brief overview of the method is presented, while the development of the linear interaction energy with continuum electrostatics (LIECE) model for the WNV protease is presented in the section Results and Discussion
Summary
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 has good potential as lead compound for further development to combat West Nile virus infections
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