Rational Drug Discovery: Ellagic Acid As A Potent Dual-target Inhibitor against Hepatitis C Virus Genotype 3 (HCV G3) NS3 Enzymes.
Chem Biol Drug Des. 2020 Jul 13. Epub 2020 Jul 13. PMID: 32657543
See Khai Lim
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= 40.37± 5.47 nM and 6.58 ± 0.99 µM 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 withan ECof 19.05µM. The dual-target inhibitor, ellagic acid was determined as the second most potent (EC= 32.37µM) 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).