Ramos-Guzmán Carlos A, Andjelkovic Milorad, Zinovjev Kirill, Ruiz-Pernía J Javier, Tuñón Iñaki
Departamento de Química Física, Universidad de Valencia 46100 Burjassot Spain
Instituto de Materiales Avanzados, Universidad Jaume I 12071 Castelló Spain.
Chem Sci. 2023 Feb 14;14(10):2686-2697. doi: 10.1039/d2sc06584c. eCollection 2023 Mar 8.
The use of antiviral drugs can promote the appearance of mutations in the target protein that increase the resistance of the virus to the treatment. This is also the case of nirmatrelvir, a covalent inhibitor of the 3CL protease, or main protease, of SARS-CoV-2. In this work we show how the by-residue decomposition of noncovalent interactions established between the drug and the enzyme, in combination with an analysis of naturally occurring mutations, can be used to detect potential mutations in the 3CL protease conferring resistance to nirmatrelvir. We also investigate the consequences of these mutations on the reaction mechanism to form the covalent enzyme-inhibitor complex using QM/MM methods. In particular, we show that the E166V variant of the protease displays smaller binding affinity to nirmatrelvir and larger activation free energy for the formation of the covalent complex, both factors contributing to the observed resistance to the treatment with this drug. The conclusions derived from our work can be used to anticipate the consequences of the introduction of nirmatrelvir in the fitness landscape of the virus and to design new inhibitors adapted to some of the possible resistance mechanisms.
使用抗病毒药物会促使靶蛋白出现突变，从而增加病毒对治疗的抗性。新冠病毒 3CL 蛋白酶（即主要蛋白酶）的共价抑制剂奈玛特韦也是如此。在这项工作中，我们展示了如何通过分析药物与酶之间非共价相互作用的残基分解，并结合对自然发生突变的分析，来检测 3CL 蛋白酶中赋予对奈玛特韦抗性的潜在突变。我们还使用量子力学/分子力学（QM/MM）方法研究了这些突变对形成共价酶 - 抑制剂复合物反应机制的影响。特别是，我们表明蛋白酶的 E166V 变体与奈玛特韦的结合亲和力较小，形成共价复合物的活化自由能较大，这两个因素共同导致了对该药物治疗的抗性。我们工作得出的结论可用于预测在病毒适应度格局中引入奈玛特韦的后果，并设计适应某些可能抗性机制的新型抑制剂。
