Multiscale Simulations of the Covalent Inhibition of the SARS-CoV-2 Main Protease: Four Compounds and Three Reaction Mechanisms,Journal of the American Chemical Society

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Multiscale Simulations of the Covalent Inhibition of the SARS-CoV-2 Main Protease: Four Compounds and Three Reaction Mechanisms
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-06-09 , DOI: 10.1021/jacs.3c02229
Bella L Grigorenko _{1,

2} , Igor V Polyakov _{1,

2} , Maria G Khrenova _{1,

3} , Goran Giudetti ₄ , Shirin Faraji ₅ , Anna I Krylov ₄ , Alexander V Nemukhin _{1,

2}

Affiliation

We report the results of computational modeling of the reactions of the SARS-CoV-2 main protease (M^Pro) with four potential covalent inhibitors. Two of them, carmofur and nirmatrelvir, have shown experimentally the ability to inhibit M^Pro. Two other compounds, X77A and X77C, were designed computationally in this work. They were derived from the structure of X77, a non-covalent inhibitor forming a tight surface complex with M^Pro. We modified the X77 structure by introducing warheads capable of reacting with the catalytic cysteine residue in the M^Pro active site. The reaction mechanisms of the four molecules with M^Pro were investigated by quantum mechanics/molecular mechanics (QM/MM) simulations. The results show that all four compounds form covalent adducts with the catalytic cysteine Cys 145 of M^Pro. From the chemical perspective, the reactions of these four molecules with M^Pro follow three distinct mechanisms. The reactions are initiated by a nucleophilic attack of the thiolate group of the deprotonated cysteine residue from the catalytic dyad Cys145–His41 of M^Pro. In the case of carmofur and X77A, the covalent binding of the thiolate to the ligand is accompanied by the formation of the fluoro-uracil leaving group. The reaction with X77C follows the nucleophilic aromatic substitution S_NAr mechanism. The reaction of M^Pro with nirmatrelvir (which has a reactive nitrile group) leads to the formation of a covalent thioimidate adduct with the thiolate of the Cys145 residue in the enzyme active site. Our results contribute to the ongoing search for efficient inhibitors of the SARS-CoV-2 enzymes.

中文翻译：

SARS-CoV-2 主要蛋白酶共价抑制的多尺度模拟：四种化合物和三种反应机制

我们报告了 SARS-CoV-2 主要蛋白酶 (M ^Pro ) 与四种潜在共价抑制剂反应的计算模型结果。^{其中两种药物，卡莫氟和尼尔马韦，已通过实验显示出抑制 M Pro 的}能力。本工作中通过计算设计了另外两种化合物 X77A 和 X77C。它们源自 X77 的结构，X77 是一种与 M ^Pro形成紧密表面复合物的非共价抑制剂。^{我们通过引入能够与 M Pro}活性位点中的催化半胱氨酸残基反应的弹头来修改 X77 结构。通过量子力学/分子力学（QM/MM）模拟研究了四种分子与M ^{Pro的反应机理。}^{结果表明，所有四种化合物均与 M Pro}的催化半胱氨酸 Cys 145 形成共价加合物。从化学角度来看，这四种分子与 M ^Pro的反应遵循三种不同的机制。^{该反应由 M Pro}催化二元体 Cys145-His41 的去质子化半胱氨酸残基的硫醇基团的亲核攻击引发。在卡莫氟和X77A的情况下，硫醇盐与配体的共价结合伴随着氟尿嘧啶离去基团的形成。与 X77C 的反应遵循亲核芳族取代 S _N Ar 机理。^{M Pro}与 nirmatrelvir（具有反应性腈基团）的反应导致与酶活性位点的 Cys145 残基的硫醇盐形成共价硫代亚氨酸盐加合物。我们的研究结果有助于持续寻找 SARS-CoV-2 酶的有效抑制剂。

更新日期：2023-06-09

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