Rational drug discovery: Ellagic acid as a potent dual‐target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes

Structure‐based virtual screening (SBVS) has served as a popular strategy for rational drug discovery. In this study, we aimed to discover novel benzopyran‐based inhibitors that targeted the NS3 enzymes (NS3/4A protease and NS3 helicase) of HCV G3 using a combination of in silico and in vitro approaches. With the aid of SBVS, six novel compounds were discovered to inhibit HCV G3 NS3/4A protease and two phytochemicals (ellagic acid and myricetin) were identified as dual‐target inhibitors that inhibited both NS3/4A protease and NS3 helicase in vitro (IC 50 = 40.37 ± 5.47 n m and 6.58 ± 0.99 µ m , respectively). Inhibitory activities against the replication of HCV G3 replicons were further assessed in a cell‐based system with four compounds showed dose‐dependent inhibition. Compound P8 was determined to be the most potent compound from the cell‐based assay with an EC 50 of 19.05 µ m . The dual‐target inhibitor, ellagic acid, was determined as the second most potent (EC 50 = 32.37 µ m ) and the most selective in its inhibitory activity against the replication of HCV replicons, without severely affecting the viability of the host cells (selectivity index > 6.18).