Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2
文献类型:期刊论文
作者 | Ren, Pengxuan1; Yu, Changyue2; Zhang, Ruxue3; Nie, Tianqing2,4; Hu, Qiaoyu1,6; Li, Hui2,4; Zhang, Xianglei1; Zhang, Xueyuan1; Li, Shiwei1; Liu, Lu1 |
刊名 | European journal of medicinal chemistry |
出版日期 | 2023-05-05 |
卷号 | 249页码:115129 |
ISSN号 | 1768-3254 |
DOI | 10.1016/j.ejmech.2023.115129 |
文献子类 | Article |
英文摘要 | The 3C-like protease (3CLpro) is essential for the replication and transcription of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making it a promising target for the treatment of corona virus disease 2019 (COVID-19). In this study, a series of 2,3,5-substituted [1,2,4]-thiadiazole analogs were discovered to be able to inhibit 3CLpro as non-peptidomimetic covalent binders at submicromolar levels, with IC50 values ranging from 0.118 to 0.582 muM. Interestingly, these compounds were also shown to inhibit PLpro with the same level of IC50 values, but had negligible effect on proteases such as chymotrypsin, cathepsin B, and cathepsin L. Subsequently, the antiviral abilities of these compounds were evaluated in cell-based assays, and compound 6g showed potent antiviral activity with an EC50 value of 7.249 muM. It was proposed that these compounds covalently bind to the catalytic cysteine 145 via a ring-opening metathesis reaction mechanism. To understand this covalent-binding reaction, we chose compound 6a, one of the identified hit compounds, as a representative to investigate the reaction mechanism in detail by combing several computational predictions and experimental validation. The process of ring-opening metathesis was theoretically studied using quantum chemistry calculations according to the transition state theory. Our study revealed that the 2,3,5-substituted [1,2,4]-thiadiazole group could covalently modify the catalytic cysteine in the binding pocket of 3CLpro as a potential warhead. Moreover, 6a was a known GPCR modulator, and our study is also a successful computational method-based drug-repurposing study. |
WOS关键词 | 2,3,5-substituted [1,2,4]-thiadiazole ; 3CL(pro) ; Covalent inhibitors ; Ring-opening metathesis ; SARS-CoV-2 ; Warhead |
语种 | 英语 |
WOS记录号 | MEDLINE: 36702052 |
源URL | [http://119.78.100.183/handle/2S10ELR8/309619] |
专题 | 新药研究国家重点实验室 |
作者单位 | 1.School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China 2.State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China 3.State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China 4.School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China 5.School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China 6.East China Normal University, Innovation Center for AI and Drug Discovery, Shanghai, 200062, China 7.School of Information Science and Technology, ShanghaiTech University, Shanghai, 201210, China 8.School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China |
推荐引用方式 GB/T 7714 | Ren, Pengxuan,Yu, Changyue,Zhang, Ruxue,et al. Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2[J]. European journal of medicinal chemistry,2023,249:115129. |
APA | Ren, Pengxuan.,Yu, Changyue.,Zhang, Ruxue.,Nie, Tianqing.,Hu, Qiaoyu.,...&Bai, Fang.(2023).Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2.European journal of medicinal chemistry,249,115129. |
MLA | Ren, Pengxuan,et al."Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2".European journal of medicinal chemistry 249(2023):115129. |
入库方式: OAI收割
来源:上海药物研究所
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