Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States.
Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States.
J Chem Inf Model. 2021 Feb 22;61(2):1020-1032. doi: 10.1021/acs.jcim.0c01457. Epub 2021 Feb 4.
Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 (evere cute espiratory yndrome ronairus 2). This highly pathogenic virus has to date caused >71 million infections and >1.6 million deaths in >180 countries. Several vaccines and drugs are being studied as possible treatments or prophylactics of this viral infection. M3CLpro (coronavirus main cysteine protease) is a promising drug target as it has a significant role in viral replication. Here we use the X-ray crystal structure of M3CLpro in complex with boceprevir to study the dynamic changes of the protease upon ligand binding. The binding free energy was calculated for water molecules at different locations of the binding site, and molecular dynamics (MD) simulations were carried out for the M3CLpro/boceprevir complex, to thoroughly understand the chemical environment of the binding site. Several HCV NS3/4a protease inhibitors were tested against M3CLpro. Specifically, asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir all showed inhibitory effects on M3CLpro. Molecular docking and MD simulations were then performed to investigate the effects of these ligands on M3CLpro and to provide insights into the chemical environment of the ligand binding site. Our findings and observations are offered to help guide the design of possible potent protease inhibitors and aid in coping with the COVID-19 pandemic.
目前，整个人类群体都处于由 SARS-CoV-2（严重急性呼吸综合征冠状病毒 2）引起的全球大流行之中。这种高致病性病毒迄今为止已在 180 多个国家造成超过 7100 万例感染和超过 160 万人死亡。目前正在研究几种疫苗和药物，以作为这种病毒感染的潜在治疗或预防方法。M3CLpro（冠状病毒主要半胱氨酸蛋白酶）是一个很有前途的药物靶点，因为它在病毒复制中起着重要作用。在这里，我们使用 M3CLpro 与 boceprevir 复合物的 X 射线晶体结构来研究配体结合时蛋白酶的动态变化。计算了结合位点不同位置的水分子的结合自由能，并对 M3CLpro/boceprevir 复合物进行了分子动力学（MD）模拟，以彻底了解结合位点的化学环境。对几种 HCV NS3/4a 蛋白酶抑制剂进行了针对 M3CLpro 的测试。具体而言，asunaprevir、narlaprevir、paritaprevir、simeprevir 和 telaprevir 均对 M3CLpro 表现出抑制作用。然后进行了分子对接和 MD 模拟，以研究这些配体对 M3CLpro 的影响，并深入了解配体结合位点的化学环境。我们的发现和观察结果旨在帮助指导设计可能有效的蛋白酶抑制剂，并帮助应对 COVID-19 大流行。
