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Structure-guided design and photochemical synthesis of new carbamo (dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro

文献类型：期刊论文

作者Yin, De-Hang2; Xin, Jie3; Chen, Shizhao1,4; Li, Shuai-Shuai2; Li, Zi-Ying2; Meng, Jin-Xi2; Lin, Yue-Chi2; Yin, Bing-Qian2; Zhao, Cheng2; Li, Jia1,4
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2024-11-15
卷号114页码:9
关键词SARS-CoV-2 Disulfiram Carbamo(dithioperoxo)thioates Photochemistry 3CL pro
ISSN号0968-0896
DOI10.1016/j.bmc.2024.117940
通讯作者Gao, Hang(hanggao@tyut.edu.cn) ; Gao, Wen-Chao(gaowenchao@tyut.edu.cn)
英文摘要The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CLpro of SARSCoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CLpro; however, its structure lacks bonding site with active pockets of 3CLpro and its highly symmetric structure doesn't match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CLpro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5-17 folds potency against SARS-CoV-2 3CLpro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC50) values ranging from 0.14-0.47 mu M. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor to both 3CLpro (IC50 = 0.14 mu M) and PL pro (IC50 = 0.04 mu M). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CLpro. The green synthetic methodology, the privileged carbamo (dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CLpro.
WOS关键词DISULFIRAM ; ACCURACY
资助项目National Natural Science Foundation of China[22301213] ; National Natural Science Foundation of China[21901179] ; Fundamental Research Program of Shanxi Province[202103021224067] ; Fundamental Research Program of Shanxi Province[20210302124076] ; Fundamental Research Program of Shanxi Province[20210302124404]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001346630400001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/314303]  
专题中国科学院上海药物研究所
通讯作者Gao, Hang; Gao, Wen-Chao
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Taiyuan Univ Technol, Coll Chem & Chem Engn, Taiyuan 030024, Peoples R China
3.Peoples Hosp Feicheng, Feicheng 271600, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yin, De-Hang,Xin, Jie,Chen, Shizhao,et al. Structure-guided design and photochemical synthesis of new carbamo (dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2024,114:9.
APA Yin, De-Hang.,Xin, Jie.,Chen, Shizhao.,Li, Shuai-Shuai.,Li, Zi-Ying.,...&Gao, Wen-Chao.(2024).Structure-guided design and photochemical synthesis of new carbamo (dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro.BIOORGANIC & MEDICINAL CHEMISTRY,114,9.
MLA Yin, De-Hang,et al."Structure-guided design and photochemical synthesis of new carbamo (dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro".BIOORGANIC & MEDICINAL CHEMISTRY 114(2024):9.

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来源：上海药物研究所

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