In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1

作者全名："Xie, Song; Cao, Shoujing; Wu, Juhong; Xie, Zhinuo; Liu, Yu-Tsen; Fu, Wei; Zhao, Qianqian; Liu, Lin; Yang, Lin; Li, Jinyu"

作者地址："[Xie, Song; Cao, Shoujing; Wu, Juhong; Xie, Zhinuo; Fu, Wei; Li, Jinyu] Fuzhou Univ, Coll Chem, Fuzhou, Peoples R China; [Liu, Yu-Tsen] Xiamen ITG SUIS High Sch, Xiamen, Peoples R China; [Zhao, Qianqian] Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China; [Liu, Lin] Fujian Agr & Forestry Univ, Coll Life Sci, Fuzhou, Peoples R China; [Yang, Lin] Fujian Med Univ, Fujian Canc Hosp, Clin Oncol Sch, Dept Pharm, Fuzhou, Peoples R China"

通信作者："Li, JY (通讯作者)，Fuzhou Univ, Coll Chem, Fuzhou, Peoples R China.; Yang, L (通讯作者)，Fujian Med Univ, Fujian Canc Hosp, Clin Oncol Sch, Dept Pharm, Fuzhou, Peoples R China."

来源：JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001014696300001

JCR分区：Q2

影响因子：2.7

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：SARS-CoV-2; COVID-19; macrodomain; inhibitor; MD simulation; metadynamics

摘要："The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using in silico-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1-MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (-9.8 & PLUSMN; 0.3 kcal/mol) and MC5 (-9.6 & PLUSMN; 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (-8.9 & PLUSMN; 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19.Communicated by Ramaswamy H. Sarma"

基金机构："Natural Science Foundation of China [22173020]; Natural Science Foundation of Fujian Province [2019J06007]; Joint Funds for the Innovation of Science and Technology, Fujian Province [2019Y9040]"

基金资助正文："We gratefully acknowledge financial supports from the Natural Science Foundation of China (22173020), the Natural Science Foundation of Fujian Province (2019J06007) and the Joint Funds for the Innovation of Science and Technology, Fujian Province (2019Y9040)."