Elucidating Atomistic Insight into the Dynamical Responses of the SARS-CoV-2 Main Protease for the Binding of Remdesivir Analogues: Leveraging Molecular Mechanics To Decode the Inhibition Mechanism

分子动力学 化学 分子力学 范德瓦尔斯力 对接(动物) 能源景观 背景(考古学) 相互作用能 溶剂化 合理设计 配体(生物化学) 计算化学 纳米技术 分子 生物化学 生物 材料科学 受体 医学 古生物学 护理部 有机化学
作者
Pabitra Narayan Samanta,D. Majumdar,Jerzy Leszczyński
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
卷期号:63 (11): 3404-3422 被引量:1
标识
DOI:10.1021/acs.jcim.3c00105
摘要

To combat mischievous coronavirus disease followed by continuous upgrading of therapeutic strategy against the antibody-resistant variants, the molecular mechanistic understanding of protein-drug interactions is a prerequisite in the context of target-specific rational drug development. Herein, we attempt to decipher the structural basis for the inhibition of SARS-CoV-2 main protease (Mpro) through the elemental analysis of potential energy landscape and the associated thermodynamic and kinetic properties of the enzyme-inhibitor complexes using automated molecular docking calculations in conjunction with classical force field-based molecular dynamics (MD) simulations. The crux of the scalable all-atom MD simulations consummated in explicit solvent media is to capture the structural plasticity of the viral enzyme due to the binding of remdesivir analogues and ascertain the subtle interplay of noncovalent interactions in stabilizing specific conformational states of the receptor that controls the biomolecular processes related to the ligand binding and dissociation kinetics. To unravel the critical role of modulation of the ligand scaffold, we place further emphasis on the estimation of binding free energy as well as the energy decomposition analysis by employing the generalized Born and Poisson-Boltzmann models. The estimated binding affinities are found to vary between -25.5 and -61.2 kcal/mol. Furthermore, the augmentation of inhibitory efficacy of the remdesivir analogue crucially stems from the van der Waals interactions with the active site residues of the protease. The polar solvation energy contributes unfavorably to the binding free energy and annihilates the contribution of electrostatic interactions as derived from the molecular mechanical energies.
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