The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 1.4 million deaths worldwide. Repurposing existing drugs offers the fastest opportunity to identify new indications for existing drugs as a stable solution against coronavirus disease 2019 (COVID-19). The SARS-CoV-2 main protease (M^pro) is a critical target for designing potent antiviral agents against COVID-19. In this study, we identify potential inhibitors against COVID-19, using an amalgam of virtual screening, molecular dynamics (MD) simulations, and binding-free energy approaches from the Korea Chemical Bank drug repurposing (KCB-DR) database. The database screening of KCB-DR resulted in 149 binders. The dynamics of protein-drug complex formation for the seven top scoring drugs were investigated through MD simulations. Six drugs showed stable binding with active site of SARS-CoV-2 M^pro indicated by steady RMSD of protein backbone atoms and potential energy profiles. Furthermore, binding free energy calculations suggested the community-acquired bacterial pneumonia drug ceftaroline fosamil and the hepatitis C virus (HCV) protease inhibitor telaprevir are potent inhibitors against M^pro. Molecular dynamics and interaction analysis revealed that ceftaroline fosamil and telaprevir form hydrogen bonds with important active site residues such as Thr24, Thr25, His41, Thr45, Gly143, Ser144, Cys145, and Glu166 that is supported by crystallographic information of known inhibitors. Telaprevir has potential side effects, but its derivatives have good pharmacokinetic properties and are suggested to bind M^pro. We suggest the telaprevir derivatives and ceftaroline fosamil bind tightly with SARS-CoV-2 M^pro and should be validated through preclinical testing.

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 已在全球造成超过 140 万人死亡。重新利用现有药物提供了最快的机会来确定现有药物的新适应症，作为对抗 2019 冠状病毒病 (COVID-19) 的稳定解决方案。SARS-CoV-2 主要蛋白酶 (M ^pro) 是设计针对 COVID-19 的强效抗病毒剂的关键目标。在这项研究中，我们使用来自韩国化学银行药物再利用 (KCB-DR) 数据库的虚拟筛选、分子动力学 (MD) 模拟和无结合能量方法的结合，确定了针对 COVID-19 的潜在抑制剂。KCB-DR 的数据库筛选产生了 149 个结合物。通过 MD 模拟研究了七种得分最高的药物的蛋白质-药物复合物形成的动力学。^{六种药物显示出与 SARS-CoV-2 M pro}活性位点的稳定结合由蛋白质主链原子和势能分布的稳定 RMSD 表示。此外，结合自由能计算表明，社区获得性细菌性肺炎药物 ceftaroline fosamil 和丙型肝炎病毒 (HCV) 蛋白酶抑制剂 telaprevir 是针对 M ^pro的有效抑制剂。分子动力学和相互作用分析表明，ceftaroline fosamil 和 telaprevir 与 Thr24、Thr25、His41、Thr45、Gly143、Ser144、Cys145 和 Glu166 等重要活性位点残基形成氢键，已知抑制剂的晶体学信息支持这一点。Telaprevir有潜在的副作用，但其衍生物具有良好的药代动力学特性，建议结合M ^pro. 我们建议 telaprevir 衍生物和 ceftaroline fosamil 与 SARS-CoV-2 M ^pro紧密结合，并应通过临床前测试进行验证。