TY - JOUR
KW - Models, Molecular
KW - Protein Binding
KW - Viral Nonstructural Proteins
KW - West Nile virus
KW - Antiviral Agents
KW - Serine Proteases
KW - Serine Proteinase Inhibitors
KW - Thiourea
AU - D. Ekonomiuk
AU - X.-C. Su
AU - K. Ozawa
AU - C. Bodenreider
AU - S. P. Lim
AU - Z. Yin
AU - T. H. Keller
AU - D. Beer
AU - V. Patel
AU - G. Otting
AU - A. Caflisch
AU - D. Huang
AB - <p><b>BACKGROUND: </b>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.</p><p><b>METHODOLOGY: </b>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 <sup>15</sup>N-HSQC NMR spectra. The inhibitory activity is further validated by an enzymatic assay and a tryptophan fluorescence quenching assay.</p><p><b>CONCLUSION: </b>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.</p>
BT - PLoS Neglected Tropical Diseases
C1 - 0105
DA - 2009
DO - 10.1371/journal.pntd.0000356
IS - 1
J2 - PLoS Negl. Trop. Dis.
LA - eng
M3 - Research Article
N2 - <p><b>BACKGROUND: </b>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.</p><p><b>METHODOLOGY: </b>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 <sup>15</sup>N-HSQC NMR spectra. The inhibitory activity is further validated by an enzymatic assay and a tryptophan fluorescence quenching assay.</p><p><b>CONCLUSION: </b>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.</p>
PY - 2009
EP - e356
T2 - PLoS Neglected Tropical Diseases
TI - Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking
VL - 3
SN - 1935-2735
ER -