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 (SARSCoV-
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 (
Mpro). Particularly, viewing the large-scale biological role of Mpro
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 Mpro.
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
Mpro.
Hence, all four identified compounds might be considered as promising candidates for future drug development specifically
targeting the SARS-CoV-2 Mpro;
however, they also need experimental assessment for a better understanding of
molecular interaction mechanisms.
