In silico Molecular Docking, Dynamics, and ADMET Analyses of Leritrelvir Targeting SARS-CoV-2 Main Protease

Abstract

The current COVID19 pandemic necessitates the development of antiviral agents targeting the SARS-CoV-2 main protease. It is one of the viral enzymes that plays a key role in reproduction. Rayitrelvir (RAY1216), a 2-ketoamide-based peptidomimetic inhibitor, is presently in clinical development. To determine the nature and dynamics of Leritrelvir (RAY1216) binding to Mpro (PDB ID: 6LU7), structure-based molecular docking and dynamics simulation were used in this study to clarify the nature and dynamic stability of Leritrelvir (RAY1216). AutoDock was used to dock, and further validation was done on the DockThor platform. The interactive analysis showed that Leritrelvir (RAY1216) was highly stably bound in the catalytic pocket (7.3 kcal/mol), which was hydrogen bonded with GLN110, HIS246, GLU240, GLN110, and PRO108 and interacted π-π with HIS246 and PHE294. Docking comparative with Nirmatrelvir, the active compound of Paxlovid, showed a similar binding affinity (ΔG = -7.16 kcal/mol) and partially overlapping binding residues, which confirmed the reliability of docking results. Conformational stability of the LeritrelvirMpro complex was confirmed by a 100ns MD that showed stable RMSD, radius of gyration, and maintained hydrogen bonding, whereas the RMSF variations were localized to flexible terminal areas. ADMET predictions (SwissADME and ProTox-II) in silico revealed good pharmacokinetics and oral bioavailability, and good toxicity. When combined, these results provide docking, dynamics, and pharmacokinetics, making Leritrelvir (RAY1216) an effective noncovalent SARS-CoV2 Mpro inhibitor. However, additional in vitro and in vivo studies are justified to establish its potential in clinical use as a next-generation therapeutic to treat COVID19.