Rational drug discovery: Ellagic acid as a potent dual-target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes
Document Type
Article
Publication Date
1-1-2021
Abstract
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 (IC50 = 40.37 +/- 5.47 nmand 6.58 +/- 0.99 mu 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 mu m. The dual-target inhibitor, ellagic acid, was determined as the second most potent (EC50 = 32.37 mu 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).
Keywords
Benzopyran, Ellagic acid, Helicase, Hepatitis C virus, NS3, 4A protease, Virtual screening
Divisions
fac_med
Funders
Universiti Malaya (BKS065-2017),Universiti Malaya (PG076-2016A)
Publication Title
Chemical Biology & Drug Design
Volume
97
Issue
1
Publisher
Wiley
Publisher Location
111 RIVER ST, HOBOKEN 07030-5774, NJ USA