Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India.
Discipline of Chemistry, Indian Institute of Technology Palakkad, Palakkad, India.
J Biomol Struct Dyn. 2021 Oct;39(16):6249-6264. doi: 10.1080/07391102.2020.1796810. Epub 2020 Jul 28.
The sudden outburst of Coronavirus disease (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a massive threat to global public health. Currently, no therapeutic drug or vaccine exists to treat COVID-19. Due to the time taking process of new drug development, drug repurposing might be the only viable solution to tackle COVID-19. RNA-dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication and hence, is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols effectively inhibit the RdRp of other RNA viruses. More importantly, polyphenols have been used as dietary supplementations for a long time and played beneficial roles in immune homeostasis. We were curious to study the binding of polyphenols with SARS-CoV-2 RdRp and assess their potential to treat COVID-19. Herein, we made a library of polyphenols that have shown substantial therapeutic effects against various diseases. They were successfully docked in the catalytic pocket of RdRp. The investigation reveals that EGCG, theaflavin (TF1), theaflavin-3'--gallate (TF2a), theaflavin-3'-gallate (TF2b), theaflavin 3,3'-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp. Further, a 150-ns molecular dynamic simulation revealed that EGCG, TF2a, TF2b, TF3 result in highly stable bound conformations with RdRp. The binding free energy components calculated by the MM-PBSA also confirm the stability of the complexes. We also performed a detailed analysis of ADME prediction, toxicity prediction, and target analysis for their druggability. Overall, our results suggest that EGCG, TF2a, TF2b, TF3 can inhibit RdRp and represent an effective therapy for COVID-19.Communicated by Ramaswamy H. Sarma.
严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）引起的冠状病毒病（COVID-19）的突然爆发，对全球公共健康构成了巨大威胁。目前，尚无治疗 COVID-19 的药物或疫苗。由于新药研发过程耗时较长，药物再利用可能是应对 COVID-19 的唯一可行解决方案。RNA 依赖性 RNA 聚合酶（RdRp）催化 SARS-CoV-2 RNA 复制，因此是抗病毒药物设计的明显靶点。有趣的是，几种植物来源的多酚有效抑制其他 RNA 病毒的 RdRp。更重要的是，多酚长期以来一直被用作膳食补充剂，并在免疫稳态中发挥有益作用。我们很好奇地研究了多酚与 SARS-CoV-2 RdRp 的结合，并评估了它们治疗 COVID-19 的潜力。在此，我们制作了一个多酚库，这些多酚对各种疾病显示出显著的治疗效果。它们成功地对接在 RdRp 的催化口袋中。研究表明，EGCG、茶黄素（TF1）、茶黄素-3'-没食子酸酯（TF2a）、茶黄素-3'-没食子酸酯（TF2b）、茶黄素-3,3'-二没食子酸酯（TF3）、橙皮苷、槲皮素和杨梅素强烈结合到 RdRp 的活性位点。此外，150ns 分子动力学模拟表明，EGCG、TF2a、TF2b、TF3 与 RdRp 形成高度稳定的结合构象。通过 MM-PBSA 计算的结合自由能成分也证实了复合物的稳定性。我们还对它们的成药性进行了详细的 ADME 预测、毒性预测和靶标分析。总的来说，我们的结果表明，EGCG、TF2a、TF2b、TF3 可以抑制 RdRp，代表了 COVID-19 的有效治疗方法。由 Ramaswamy H. Sarma 传达。
