Data_Sheet_2_Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2.docx

SARS-CoV-2 is a newly emerged coronavirus that causes a respiratory disease with variable severity and fatal consequences. It was first reported in Wuhan and subsequently caused a global pandemic. The viral spike protein binds with the ACE-2 cell surface receptor for entry, while TMPRSS2 triggers its membrane fusion. In addition, RNA dependent RNA polymerase (RdRp), 3′–5′ exoribonuclease (nsp14), viral proteases, N, and M proteins are important in different stages of viral replication. Accordingly, they are attractive targets for different antiviral therapeutic agents. Although many antiviral agents have been used in different clinical trials and included in different treatment protocols, the mode of action against SARS-CoV-2 is still not fully understood. Different potential repurposed drugs, including, chloroquine, hydroxychloroquine, ivermectin, remdesivir, and favipiravir, were screened in the present study. Molecular docking of these drugs with different SARS-CoV-2 target proteins, including spike and membrane proteins, RdRp, nucleoproteins, viral proteases, and nsp14, was performed. Moreover, the binding affinities of the human ACE-2 receptor and TMPRSS2 to the different drugs were evaluated. Molecular dynamics simulation and MM-PBSA calculation were also conducted. Ivermectin and remdesivir were found to be the most promising drugs. Our results suggest that both these drugs utilize different mechanisms at the entry and post-entry stages and could be considered potential inhibitors of SARS-CoV-2 replication.

SARS-CoV-2是一种新型冠状病毒，可引发病情严重程度不一且具有致死性后果的呼吸道疾病。该病毒首次在武汉被发现并报告，随后引发了全球大流行。病毒刺突蛋白（spike protein）通过结合ACE-2细胞表面受体介导病毒入侵，而TMPRSS2则触发其膜融合过程。此外，RNA依赖的RNA聚合酶（RNA dependent RNA polymerase, RdRp）、3′–5′ 核糖外切核酸酶（3′–5′ exoribonuclease, nsp14）、病毒蛋白酶、N蛋白与M蛋白在病毒复制的不同阶段发挥重要作用，因此成为各类抗病毒治疗药物的理想靶点。尽管已有多种抗病毒药物应用于多项临床试验并被纳入多种治疗方案，但其针对SARS-CoV-2的作用机制仍未完全明确。本研究对包括氯喹、羟氯喹、伊维菌素、瑞德西韦以及法匹拉韦在内的多种潜在老药新用药物进行了筛选。针对上述药物与不同SARS-CoV-2靶标蛋白（包括刺突蛋白、膜蛋白、RdRp、核蛋白、病毒蛋白酶以及nsp14）开展了分子对接实验。此外，本研究还评估了人ACE-2受体与TMPRSS2与各类药物的结合亲和力。同时还开展了分子动力学模拟与MM-PBSA计算。研究结果显示，伊维菌素与瑞德西韦是最具潜力的候选药物。本研究结果表明，这两种药物可在病毒入侵及入侵后阶段通过不同机制发挥作用，有望成为SARS-CoV-2复制的潜在抑制剂。