Among targets selected for studies aimed at identifying potential inhibitors against COVID-19, SARS-CoV2 main proteinase (M^pro) is highlighted. M^pro is indispensable for virus replication and is a promising target of potential inhibitors of COVID-19. Recently, monomeric SARS-CoV2 M^pro, drug repurposing, and docking methods have facilitated the identification of several potential inhibitors. Results were refined through the assessment of dimeric SARS-CoV2 M^pro, which represents the functional state of enzyme. Docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area (MM/GBSA) studies indicated that dimeric M^pro most significantly impacts binding affinity tendency compared with the monomeric state, which suggests that dimeric state is most useful when performing studies aimed at identifying drugs targeting M^pro. In this study, we extend previous research by performing docking and MD simulation studies coupled with an MM/GBSA approach to assess binding of dimeric SARS-CoV2 M^pro to 12 FDA-approved drugs (darunavir, indinavir, saquinavir, tipranavir, diosmin, hesperidin, rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin, and bortezomib), which were identified as the best candidates for the treatment of COVID-19 in some previous dockings studies involving monomeric SARS-CoV2 M^pro. This analysis identified saquinavir as a potent inhibitor of dimeric SARS-CoV2 M^pro; therefore, the compound may have clinical utility against COVID-19.

在为旨在识别 COVID-19 潜在抑制剂的研究选择的靶点中，SARS-CoV2 主要蛋白酶 (M ^pro ) 被突出显示。M ^pro对病毒复制是必不可少的，是 COVID-19 潜在抑制剂的有希望的靶点。最近，单体 SARS-CoV2 M ^pro、药物再利用和对接方法促进了几种潜在抑制剂的鉴定。通过对代表酶功能状态的二聚体 SARS-CoV2 M ^{pro的评估来完善结果。}对接和分子动力学 (MD) 模拟结合分子力学/广义玻恩表面积 (MM/GBSA) 研究表明，二聚体 M ^pro与单体状态相比，最显着影响结合亲和力趋势，这表明二聚状态在进行旨在识别靶向 M ^pro的药物的研究时最有用。在这项研究中，我们通过对接和 MD 模拟研究以及 MM/GBSA 方法来扩展先前的研究，以评估二聚体 SARS-CoV2 M ^pro与 12 种 FDA 批准的药物（地瑞那韦、茚地那韦、沙奎那韦、替拉那韦、地奥司明、橙皮苷）的结合。 , rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin 和 bortezomib)，在之前一些涉及单体 SARS-CoV2 M ^pro的对接研究中，它们被确定为治疗 COVID-19 的最佳候选药物。该分析确定沙奎那韦是二聚体 SARS-CoV2 M 的强效抑制剂^亲; 因此，该化合物可能具有抗 COVID-19 的临床效用。