Structure-based identification of SARS-CoV-2 main protease inhibitors from anti-viral specific chemical libraries: an exhaustive computational screening approach

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 (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. Graphic abstract

Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors

“…The virtual screening and molecular docking study were also conducted against the main protease of SARS-CoV-2 by taking FDA-approved drugs from the ZINC database where they have found binding energy ranges from −7.8 to −6.839 kcal/mol [99], whereas we have found epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate having binding affinities of −8.4, −8.5, and −8.8 kcal/mol. Additionally, multiple studies regarding the virtual screening and molecular docking were conducted by targeting the main protease of SARS-CoV-2 where several interactions at the active points Thr26, Leu41, Cys145, Pro168, Asn142, His164, Met49, Phe140, Met165, Glu166, Gln189, and Thr190 [99][100][101][102][103] were observed, which is similar to our findings.…”

Phytochemicals-based targeting RdRp and main protease of SARS-CoV-2 using docking and steered molecular dynamic simulation: A promising therapeutic approach for Tackling COVID-19

“…For grid generation in the case of Mpro, the information of the catalytic active site and substrate binding site residues coordinates was used as −12.0, 18.0, 65.0 Å along X-, Y- and Z-axes, respectively whereas dimension was considered as 26 × 28 × 30 Å respectively. During grid generation, careful inspection and confirmation of catalytic site residues (such as His41 and Cys145) and substrate binding site residues at an active site within the grid box were carried out [ 28 ]. The output of molecular docking poses generated for each ligand against the respective targets were ranked and selected among ligand-protein complex based on the docking scores.…”

Probing the Action of Screened Anticancer Triazole–Tetrazole Derivatives Against COVID-19 Using Molecular Docking and DFT Investigations

“…Thus, M pro necessitates the catalytic dyads Cys 145–His 41 to cleave SARS-CoV-2 polyproteins. 42,44 Hence, the interaction with the catalytic residues (His41and Cys145) is an attractive target for inhibition. Furthermore, it has been shown that the Cys44 to Pro52 residues constitute the catalytic loop, which forms the catalytic pocket, a loop that surrounds the cavity of the catalytic site in M pro .…”