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. Graphical abstract.
【저자키워드】 docking, protease, MD simulations, SARS-CoV2.,