Identification of potential COVID-19 Mpro inhibitors through covalent drug docking, molecular dynamics simulation, and MMGBSA calculation

• Published in: Scientific reports Vol. 15; no. 1; pp. 20500 - 14
• Main Authors: Abadi, Mohammad Hossein Haghir Ebrahim, Bayani, Fatemeh, Sefidbakht, Yahya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2025; Nature Portfolio
• Subjects: 631/45; 631/45/468; 631/535/1267; 631/57/2272; 692/699/255; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Computational drug design; Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - chemistry; Coronavirus 3C Proteases - metabolism; Covalent drug design; COVID-19; COVID-19 - virology; COVID-19 Drug Treatment; Humanities and Social Sciences; Humans; Ligands; Main protease (Mpro); MMGBSA; Molecular Docking Simulation; Molecular Dynamics Simulation; multidisciplinary; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Science; Science (multidisciplinary); COVID-19; Covalent drug design; Computational drug design; MMGBSA; Main protease (Mpro)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-025-05375-5

The viral main protease is a critical drug target due to its role in the SARS-CoV-2 life cycle. In this study, we evaluated 2,000 potential Mpro inhibitors recommended by the FragRep server, with a focus on interactions with the CYS145 residue. Six top candidates were selected for each of the 7JKV and 7TDU Mpro structures, and covalent molecular docking was performed using SeeSAR. We docked twelve ligands to various Mpro sites and performed 100 ns molecular dynamics (MD) simulations on the highest-scoring ligands: lig-14-23, lig-6-32, lig-2-3, lig-0101, lig-7612, lig-811, and lig-837. MD analysis, including Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and Root Mean Square Fluctuation (RMSF), confirmed the stability of the covalent complexes. Non-covalent ligands, which exhibited higher toxicity profiles, were excluded from the molecular dynamics analysis. The results indicate that lig-7612 and lig-837 form stable interactions with Mpro, suggesting their potential as drug candidates. These inhibitors exhibit pharmacological properties that could influence drug interactions and metabolism in vivo. Further safety and pharmacokinetic assessments are required for therapeutic development.