Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

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. [Figure not available: see fulltext.]