SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective

New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19. Communicated by Ramaswamy H. Sarma

针对严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的新型治疗手段已成为当务之急。当前，全球正遭受新型冠状病毒肺炎（COVID-19）引发的重大公共卫生危机。核苷酸抑制剂（nucleotide inhibitors）在对抗多种病毒感染的疗效方面已展现出诸多喜人成果。本研究通过分子建模、分子对接与动力学模拟，构建了病毒蛋白RNA依赖的RNA聚合酶（RNA-dependent RNA polymerase, RdRp）的模型，并测试其与部分临床获批药物及候选药物的结合亲和力。为确保成功复现已有研究结果、纳入RdRp的动态变化并阐明其对结合过程的影响，本研究采用分子动力学对结合计算体系进行平衡化处理。研究结果显示，索非布韦（Sofosbuvir）、利巴韦林（Ribavirin）、加利德韦（Galidesivir）、瑞德西韦（Remdesivir）、法匹拉韦（Favipiravir）、头孢呋辛（Cefuroxime）、替诺福韦（Tenofovir）以及羟氯喹（Hydroxychloroquine）均可有效结合SARS-CoV-2 RdRp。此外，塞特布韦（Setrobuvir）、YAK与IDX-184的结合效果更优，而四种新型IDX-184衍生物与SARS-CoV-2 RdRp的结合也展现出良好潜力。当前亟需筛选出可选择性结合并抑制SARS-CoV-2蛋白的药物。现有多款美国食品药品监督管理局（Food and Drug Administration, FDA）获批的抗病毒药物可为这一目标提供助力，以期降低COVID-19带来的危害。化合物2与化合物3可紧密结合SARS-CoV-2 RdRp，有望用于COVID-19的治疗。本研究由Ramaswamy H. Sarma转交。