文献类型：期刊文献

英文题名：Structure-Based Discovery of the SARS-CoV-2 Main Protease Noncovalent Inhibitors from Traditional Chinese Medicine

作者：Jin, Xiaojie[1,2,3];Zhang, Min[1];Fu, Beibei[4];Li, Mi[1];Yang, Jingyi[5];Zhang, Zhiming[6];Li, Chenghao[7];Zhang, Huijuan[1];Wu, Haibo[4];Xue, Weiwei[5];Liu, Yongqi[2,3]

第一作者：靳晓杰

通信作者：Jin, XJ[1];Jin, XJ[2];Liu, YQ[2];Jin, XJ[3];Liu, YQ[3];Xue, WW[4]

机构：[1]Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[2]Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, Lanzhou 730000, Peoples R China;[3]Gansu Univ Chinese Med, Minist Educ, Key Lab Dunhuang Med, Lanzhou 730000, Peoples R China;[4]Chongqing Univ, Sch Life Sci, Chongqing 401331, Peoples R China;[5]Chongqing Univ, Innovat Drug Res Ctr, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China;[6]Gansu Prov Hosp TCM, Lanzhou 730000, Peoples R China;[7]Yangzhou Univ, Med Coll, Yangzhou 225000, Peoples R China

第一机构：甘肃中医药大学药学院（西北中藏药协同创新中心办公室）

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, Lanzhou 730000, Peoples R China;[3]corresponding author), Gansu Univ Chinese Med, Minist Educ, Key Lab Dunhuang Med, Lanzhou 730000, Peoples R China;[4]corresponding author), Chongqing Univ, Innovat Drug Res Ctr, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China.|[10735]甘肃中医药大学;[1073501e14fb35863569f]甘肃中医药大学药学院（西北中藏药协同创新中心办公室）;

年份：2024

卷号：64

期号：4

起止页码：1319

外文期刊名：JOURNAL OF CHEMICAL INFORMATION AND MODELING

收录：;EI(收录号：20240815613562);Scopus(收录号：2-s2.0-85185576731);WOS:【SCI-EXPANDED(收录号:WOS:001173004300001)】；

基金：This work was funded by the National Natural Science Foundation of China (No. 82004202), the Gansu Provincial Science and Technology Major Project (22ZD1FA001), the Special Project of COVID-19 Emergent TCM Treatment of National Administration of Traditional Chinese Medicine (No. 2021ZYLCYJ08-3), and the Gansu Province Drug Regulatory Technical Support Special Project (No. 2021GSMPA0010)

语种：英文

外文关键词：Binding energy - Diseases - Ions - Lead compounds - Molecular dynamics - Scaffolds

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 mu M, with EC50 values of 12.25 +/- 1.68, 15.58 +/- 0.77, and 29.32 +/- 1.25 mu M, 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.