ABSTRACT
Abstract: The recent emergence of the severe acute respiratory disease caused by a novel coronavirus remains a concern posing many challenges to public health and the global economy. The resolved crystal structure of the main protease of SARS-CoV-2 or SCV2 (Mpro) has led to its identification as an attractive target for designing potent antiviral drugs. Herein, we provide a comparative molecular impact of hydroxychloroquine (HCQ), remdesivir, and β-D-N4-Hydroxycytidine (NHC) binding on SCV2 Mpro using various computational approaches like molecular docking and molecular dynamics (MD) simulation. Data analyses showed that HCQ, remdesivir, and NHC binding to SARS-CoV-2 Mpro decrease the protease loop capacity to fluctuate. These binding influences the drugs' optimum orientation in the conformational space of SCV2 Mpro and produce noticeable steric effects on the interactive residues. An increased hydrogen bond formation was observed in SCV2 Mpro–NHC complex with a decreased receptor residence time during NHC binding. The binding mode of remdesivir to SCV2 Mpro differs from other drugs having van der Waals interaction as the force stabilizing protein–remdesivir complex. Electrostatic interaction dominates in the SCV2 Mpro−HCQ and SCV2 Mpro–NHC. Residue Glu166 was highly involved in the stability of remdesivir and NHC binding at the SCV2 Mpro active site, while Asp187 provides stability for HCQ binding. © 2022, Pleiades Publishing, Ltd.