In Silico Screening for Potent Anti-HCV Compounds with Inhibitory Activities Toward the NS3/4A Protease

摘要

Hepatitis C virus (HCV) infection is a global health problem and the vaccine for this infection is currently unavailable. The HCV NS3 protein is an essential protease for viral polyprotein processing and it requires a NS4A protein as a cofactor for full activity. NS3 and its recombinant protease are currently regarded as a potential target for antiviral drugs. Therefore, finding a specific inhibitor is highly important. In this study, 50,000 peptide bond-containing compounds were screened for the ability against NS3 protease. Three compounds with free energy less than - 10 Kcal/mol were selected, in which, (Z)-2-(3-(3-ethyl-4-oxo-2-thioxothiazolidin-5-ylidene)-2-oxoindolin-1-yl)-N-(3-(trifluoromethyl)phenyl)acetamide showed the highest inhibition against NS3/4A protease. This compound was further investigated in vitro for the ability to inhibit HCV protease and revealed that it competes with substrate to bind into active sites. The kinetic parameter of NS4A-GSGS-NS3 protease with the compound indicated IC50 value of 61.1 mu M and K-i of 6.9 mu M. Thus, (Z)-2-(3-(3-ethyl-4-oxo-2-thioxothiazolidin-5-ylidene)-2-oxoindolin-1-yl)-N-(3-(trifluoromethyl)phenyl)acetamide could be a potential HCV inhibitor.