Drug Design and Development Research Group, University of Malaya, Kuala Lumpur, Malaysia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia.
Chem Biol Drug Des. 2021 Jan;97(1):28-40. doi: 10.1111/cbdd.13756. Epub 2020 Jul 26.
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 with an EC of 19.05 µm. The dual-target inhibitor, ellagic acid, was determined as the second most potent (EC = 32.37 µm) 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).
基于结构的虚拟筛选（SBVS）已成为合理药物发现的一种流行策略。在这项研究中，我们旨在使用计算机辅助和体外方法发现针对 HCV G3 的新型苯并吡喃基抑制剂，这些抑制剂针对 HCV G3 的 NS3 酶（NS3/4A 蛋白酶和 NS3 解旋酶）。借助 SBVS，发现了六种新型化合物可抑制 HCV G3 NS3/4A 蛋白酶，两种植物化学物质（鞣花酸和杨梅素）被鉴定为双重靶标抑制剂，可在体外抑制 NS3/4A 蛋白酶和 NS3 解旋酶（IC 50 分别为 40.37 ± 5.47nm 和 6.58 ± 0.99µm）。进一步在基于细胞的系统中评估了四种化合物对 HCV G3 复制子复制的抑制活性，结果表明这四种化合物具有剂量依赖性抑制作用。在细胞测定中，化合物 P8 被确定为最有效的化合物，EC 50 为 19.05µm。双重靶标抑制剂鞣花酸的抑制活性次之（EC 50 为 32.37µm），对 HCV 复制子的复制具有最高的选择性，而对宿主细胞的活力影响不大（选择性指数> 6.18）。
