Department of Pharmaceutical Chemistry, Global Institute of Pharmaceutical Education and Research, Kashipur-244713,India.
Comb Chem High Throughput Screen. 2022;25(4):702-719. doi: 10.2174/1386207324666210121111921.
Hepatitis C Virus (HCV) is very dreadful as it can attack an estimated 71 million people around the world. The World Health Organization (WHO) reported that every year about 399000 people die due to HCV caused by chronic cirrhosis and liver cancer globally. There are many drugs available for the treatment of HCV. But drug resistance and toxicity are major issues. The quest for potential drugs utilizing repositioning would be a very useful and economical method to combat HCV.
One of the most common HCV targets is RNA-dependent RNA polymerase (RdRp). The RdRp is common in HCV, Dengue virus (DENV), Zika virus (ZIKV), and Yellow fever virus (YFV) belonging to the same family of Flaviviridae. An attempt has been made in the present study to reposition different DENV, ZIKV, and YFV RdRp inhibitors against HCV NS5B polymerase utilizing structure-based molecular docking which explores the affinity and mode of binding of these RdRp inhibitors.
Several 87 compounds having dengue, yellow fever and zika RdRp inhibitory activities have been taken into consideration for the screening of potential RdRp leads utilizing docking simulation, which focuses on the affinity and mode of binding of sofosbuvir diphosphate, a standard HCV, RdRp inhibitor.
The compounds 6 (N-sulfonylanthranilic acid derivative), 17 (R1479), 20 (DMB220), 23 (FD-83-KI26), 40 (CCG-7648), 50 (T-1106), 65 (mycophenolic acid), and 69 (DMB213) exhibited docking score within the range of -7.602 to -8.971 Kcal/Mol having almost same mode of interaction as compared to the reference drug molecule. The drugs mentioned above possess satisfactory affinity to bind the hepatitis C viral RdRp and thus may be used to treat the disease. Therefore, these predicted compounds may be potential leads for further testing of anti HCV activity and can be repurposed to combat HCV. The high throughput shotgun of drug repurposing utilizing structure-based docking simulation freeware would be a cost-effective way to screen the potential anti-HCV leads.
丙型肝炎病毒（HCV）非常可怕，因为它可能会感染全球约 7100 万人。世界卫生组织（WHO）报告称，每年约有 39.9 万人因全球慢性肝硬化和肝癌导致的 HCV 而死亡。有许多药物可用于治疗 HCV。但是，耐药性和毒性是主要问题。利用药物再定位寻找潜在药物将是对抗 HCV 的非常有用和经济的方法。
HCV 的最常见靶标之一是 RNA 依赖性 RNA 聚合酶（RdRp）。 RdRp 在 HCV、登革热病毒（DENV）、寨卡病毒（ZIKV）和黄热病病毒（YFV）中很常见，它们都属于黄病毒科。本研究尝试利用结构基的分子对接来重新定位针对 HCV NS5B 聚合酶的不同 DENV、ZIKV 和 YFV RdRp 抑制剂，以探索这些 RdRp 抑制剂的亲和力和结合模式。
考虑了 87 种具有登革热、黄热病和寨卡 RdRp 抑制活性的化合物，以进行基于对接模拟的潜在 RdRp 先导化合物筛选，该模拟重点关注 HCV RdRp 抑制剂索磷布韦二磷酸的亲和力和结合模式。
化合物 6（N-磺酰基邻氨基苯甲酸衍生物）、17（R1479）、20（DMB220）、23（FD-83-KI26）、40（CCG-7648）、50（T-1106）、65（霉酚酸）和 69（DMB213）的对接评分在-7.602 至-8.971 Kcal/mol 范围内，其相互作用模式与参考药物分子几乎相同。上述药物与丙型肝炎病毒 RdRp 具有令人满意的亲和力，因此可能用于治疗该疾病。因此，这些预测的化合物可能是进一步测试抗 HCV 活性的潜在先导化合物，并可重新用于对抗 HCV。利用基于结构的对接模拟免费软件进行高通量药物再利用筛选将是一种经济有效的筛选潜在抗 HCV 先导化合物的方法。
