Exploring potential SARS-CoV-2 Mpro non-covalent inhibitors through docking, pharmacophore profile matching, molecular dynamic simulation, and MM-GBSA

• Published in: Journal of molecular modeling Vol. 29; no. 5; p. 138
• Main Authors: Shi, Yunfan, Dong, Liting, Ju, Zhuang, Li, Qiufu, Cui, Yanru, Liu, Yiran, He, Jiaoyu, Ding, Xianping
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2023; Springer Nature B.V
• Subjects: Binding; Binding energy; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; COVID-19; Endopeptidases; Free energy; Gibbs free energy; Humans; Inhibitors; Mathematical analysis; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular Medicine; Original Paper; pharmacology; Pharmacophore; Protease Inhibitors - pharmacology; proteinases; SARS-CoV-2; Screening; Severe acute respiratory syndrome coronavirus 2; Simulation; Theoretical and Computational Chemistry; Workflow; Virtual screening; 3CLpro; MM-GBSA; MD
• ISSN: 1610-2940; 0948-5023; 0948-5023
• DOI: 10.1007/s00894-023-05534-3

Context In the replication of SARS-CoV-2, the main protease (Mpro/3CLpro) is significant. It is conserved in a number of novel coronavirus variations, and no known human proteases share its cleavage sites. Therefore, 3CLpro is an ideal target. In the report, we screened five potential inhibitors (1543, 2308, 3717, 5606, and 9000) of SARS-CoV-2 Mpro through a workflow. The calculation of MM-GBSA binding free energy showed that three of the five potential inhibitors (1543, 2308, 5606) had similar inhibitor effects to X77 against Mpro of SARS-CoV-2. In conclusion, the manuscript lays the groundwork for the design of Mpro inhibitors. Methods In the virtual screening phase, we used structure-based virtual screening (Qvina2.1) and ligand-based virtual screening (AncPhore). In the molecular dynamic simulation part, we used the Amber14SB + GAFF force field to perform molecular dynamic simulation of the complex for 100 ns (Gromacs2021.5) and performed MM-GBSA binding free energy calculation according to the simulation trajectory. Graphical Abstract