School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Taiwan.
Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
Phys Chem Chem Phys. 2022 Sep 28;24(37):22898-22904. doi: 10.1039/d2cp02882d.
Coronavirus 3C-like protease (3CLpro) is found in SARS-CoV-2 virus, which causes COVID-19. 3CLpro controls virus replication and is a major target for target-based antiviral discovery. As reported by Pfizer, Nirmatrelvir (PF-07321332) is a competitive protein inhibitor and a clinical candidate for orally delivered medication. However, the binding mechanisms between Nirmatrelvir and 3CLpro complex structures remain unknown. This study incorporated ligand Gaussian accelerated molecular dynamics, the one-dimensional and two-dimensional potential of mean force, normal molecular dynamics, and Kramers' rate theory to determine the binding and dissociation rate constants ( and ) associated with the binding of the 3CLpro protein to the Nirmatrelvir inhibitor. The proposed approach addresses the challenges in designing small-molecule antiviral drugs.
冠状病毒 3C 样蛋白酶（3CLpro）存在于引发 COVID-19 的 SARS-CoV-2 病毒中。3CLpro 控制着病毒的复制，是基于靶点的抗病毒药物发现的主要靶点。辉瑞公司报告称，奈玛特韦（PF-07321332）是一种竞争性蛋白酶抑制剂，也是一种用于口服给药的临床候选药物。然而，奈玛特韦与 3CLpro 复合物结构之间的结合机制尚不清楚。本研究结合配体高斯加速分子动力学、一维和二维平均力势能、常规分子动力学和克拉默速率理论，确定了 3CLpro 蛋白与奈玛特韦抑制剂结合的结合和离解速率常数（ 和 ）。所提出的方法解决了设计小分子抗病毒药物的挑战。
