Identifying Inhibitor-SARS-CoV2-3CL<sup>pro</sup> Binding Mechanism Through Molecular Docking, GaMD Simulations, Correlation Network Analysis and MM-GBSA Calculations

Identifying Inhibitor-SARS-CoV2-3CL<sup>pro</sup> Binding Mechanism Through Molecular Docking, GaMD Simulations, Correlation Network Analysis and MM-GBSA Calculations

The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CL<sup>pro</sup>, is crucial in the virus’s life cycle and plays a pivotal role in COVID-19. Understanding how small molecules inhibit 3CL<sup>pro</sup>’s activity is vital for de...

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Bibliographic Details
Main Authors: Jianzhong Chen, Jian Wang, Wanchun Yang, Lu Zhao, Xiaoyan Xu
Format: Article
Language:English
Published: MDPI AG 2025-02-01
Series:Molecules
Subjects:
SARS-CoV2-3CL<sup>pro</sup>
GaMD simulations
correlation network analysis
normal mode analysis
MM-GBSA
Online Access:https://www.mdpi.com/1420-3049/30/4/805
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Summary:The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CL<sup>pro</sup>, is crucial in the virus’s life cycle and plays a pivotal role in COVID-19. Understanding how small molecules inhibit 3CL<sup>pro</sup>’s activity is vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to enhance the sampling of 3CL<sup>pro</sup> conformations and conducted correlation network analysis (CNA) to explore the interactions between different structural domains. Our findings indicate that a CNA-identified node in domain II of 3CL<sup>pro</sup> acts as a conduit, transferring conformational changes from the catalytic regions in domains I and II, triggered by the binding of inhibitors (7YY, 7XB, and Y6G), to domain III, thereby modulating 3CL<sup>pro</sup>’s activity. Normal mode analysis (NMA) and principal component analysis (PCA) revealed that inhibitor binding affects the structural flexibility and collective movements of the catalytic sites and domain III, influencing 3CL<sup>pro</sup>’s function. The binding free energies, predicted by both MM-GBSA and QM/MM-GBSA methods, showed a high correlation with experimental data, validating the reliability of our analyses. Furthermore, residues L27, H41, C44, S46, M49, N142, G143, S144, C145, H163, H164, M165, and E166, identified through residue-based free energy decomposition, present promising targets for the design of anti-COVID-19 drugs and could facilitate the development of clinically effective 3CL<sup>pro</sup> inhibitors.
ISSN:1420-3049

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