Abstract Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease (M pro ). Particularly, viewing the large-scale biological role of M pro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-dock and MM-GBSA cut-off scores as −8.00 and −45.00 kcal/mol, chemical space has been further reduced. Exhaustive molecular binding interactions analyses and various pharmacokinetics profiles assessment suggested four compounds (ChemDiv_D658-0159, ChemDiv_F431-0433, Enamine_Z3019991843 and Asinex_LAS_51389260) as potent inhibitors/modulators of SARS-CoV-2 M pro . In-depth protein–ligand interactions stability in the dynamic state has been evaluated by 100 ns molecular dynamics (MD) simulation studies along with MM-GBSA-based binding free energy estimations of entire simulation trajectories that have revealed strong binding affinity of all identified compounds towards M pro . Hence, all four identified compounds might be considered as promising candidates for future drug development specifically targeting the SARS-CoV-2 M pro ; however, they also need experimental assessment for a better understanding of molecular interaction mechanisms. Graphic abstract
【저자키워드】 SARS-CoV-2, main protease, molecular docking, MM-GBSA, Virtual screening, molecular dynamics, 【초록키워드】 COVID-19, Treatment, coronavirus disease, coronavirus, protocol, Mortality, docking, virus, binding free energy, SARS-CoV-2 main protease, binding affinity, Anti-viral, Health, stability, Measures, outbreak, viral replication, trajectory, mechanisms, molecular, anti-viral drug, compounds, Interaction, Analysis, Hierarchical, acute respiratory syndrome, Abstract, profile, Compound, M pro, candidate, molecular interaction, cut-off, Simulation study, binding interaction, identify, performed, collected, reported, evaluated, reduced, suggested, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2 main protease, Anti-viral, inhibitor, approach,