DOI
DOI: 10.1021/acs.jcim.3c01327
Structure-Based Discovery of the SARS-CoV-2 Main Protease Noncovalent Inhibitors from Traditional Chinese Medicine
作者地址
College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China
通讯作者
Xiaojie Jin; Weiwei Xue; Yongqi Liu
来源期刊
Journal of Chemical Information and Modeling
摘要
Traditional Chinese medicine (TCM) has been extensively employed for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is demand for discovering more SARS-CoV-2 Mpro inhibitors with diverse scaffolds to optimize anti-SARS-CoV-2 lead compounds. In this study, comprehensive in silico and in vitro assays were utilized to determine the potential inhibitors from TCM compounds against SARS-CoV-2 Mpro, which is an important therapeutic target for SARS-CoV-2. The ensemble docking analysis of 18263 TCM compounds against 15 SARS-CoV-2 Mpro conformations identified 19 TCM compounds as promising candidates. Further in vitro testing validated three compounds as inhibitors of SARS-CoV-2 Mpro and showed IC50 values of 4.64 ± 0.11, 7.56 ± 0.78, and 11.16 ± 0.26 μM, with EC50 values of 12.25 ± 1.68, 15.58 ± 0.77, and 29.32 ± 1.25 μM, respectively. Molecular dynamics (MD) simulations indicated that the three complexes remained stable over the last 100 ns of production run. An analysis of the binding mode revealed that the active compounds occupy different subsites (S1, S2, S3, and S4) of the active site of SARS-CoV-2 Mpro via specific poses through noncovalent interactions with key amino acids (e.g., HIS 41, ASN 142, GLY 143, MET 165, GLU 166, or GLN 189). Overall, this study provides evidence indicating that the three natural products obtained from TCM could be further used for anti-COVID-19 research, justifying the investigation of Chinese herbal medicinal ingredients as bioactive constituents for therapeutic targets.
资助信息
State Administration of Traditional Chinese Medicine of the People's Republic of China (82004202); National Natural Science Foundation of China (NSFC) (22ZD1FA001); Gansu Provincial Science and Technology Major Project (2021ZYLCYJ08-3); Special Project of COVID-19 Emergent TCM Treatment of National Administration of Traditional Chinese Medicine (2021GSMPA0010); Gansu Province Drug Regulatory Technical Support Special Project
资助机构
国家中医药管理局
;
国家自然科学基金委
;
甘肃省科技厅
;
甘肃省药品监督管理局
WOS学科分类
Chemistry, Medicinal
;
Chemistry, Multidisciplinary
;
Computer Science, Information Systems
;
Computer Science, Interdisciplinary Applications
附件
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Structure-Based Discovery of the SARS-CoV-2 Main Protease Noncovalent Inhibitors from Traditional Chinese Medicine.pdf
8.83 MB
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