利用光谱和微尺度热电泳技术合成硫代氨基脲类SARS-CoV-2 Mpro抑制剂及评价

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Leyao Chen, Xinluan Lv, Xiaoyu Chang, Ruiyong Wang
{"title":"利用光谱和微尺度热电泳技术合成硫代氨基脲类SARS-CoV-2 Mpro抑制剂及评价","authors":"Leyao Chen,&nbsp;Xinluan Lv,&nbsp;Xiaoyu Chang,&nbsp;Ruiyong Wang","doi":"10.1002/ardp.70089","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>The SARS-CoV-2 pandemic has spurred global efforts to develop therapeutic approaches. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and a key target for therapeutic development. In this study, 22 thiosemicarbazone derivatives were synthesized. Enzyme activity assays showed compound <b>3c</b> exhibited obvious inhibition of Mpro, with an IC<sub>50</sub> value of 3.89 μM. The interaction mechanisms between thiosemicarbazone derivatives and Mpro were investigated using synchronous fluorescence, three-dimensional fluorescence, and circular dichroism spectroscopy. The fluorescence results indicate that static quenching is predominant. The equilibrium dissociation constant (<i>K</i><sub>d</sub>) of 2.3 μM between <b>3c</b> and Mpro was obtained by microscale thermophoresis. This <i>K</i><sub>d</sub> value demonstrates the binding affinity of <b>3c</b> for Mpro, consistent with the spectral results. Meanwhile, the binding modes and stability of thiosemicarbazone derivatives with Mpro were evaluated through molecular docking and molecular dynamics simulations, which also confirmed the stable binding between compound <b>3c</b> and Mpro. This study provides valuable insights into the interaction mechanism between thiosemicarbazone derivatives and Mpro and provides clues for the design of Mpro inhibitors.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis and Evaluation of Thiosemicarbazone Inhibitors for SARS-CoV-2 Mpro by Spectroscopy and Microscale Thermophoresis\",\"authors\":\"Leyao Chen,&nbsp;Xinluan Lv,&nbsp;Xiaoyu Chang,&nbsp;Ruiyong Wang\",\"doi\":\"10.1002/ardp.70089\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>The SARS-CoV-2 pandemic has spurred global efforts to develop therapeutic approaches. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and a key target for therapeutic development. In this study, 22 thiosemicarbazone derivatives were synthesized. Enzyme activity assays showed compound <b>3c</b> exhibited obvious inhibition of Mpro, with an IC<sub>50</sub> value of 3.89 μM. The interaction mechanisms between thiosemicarbazone derivatives and Mpro were investigated using synchronous fluorescence, three-dimensional fluorescence, and circular dichroism spectroscopy. The fluorescence results indicate that static quenching is predominant. The equilibrium dissociation constant (<i>K</i><sub>d</sub>) of 2.3 μM between <b>3c</b> and Mpro was obtained by microscale thermophoresis. This <i>K</i><sub>d</sub> value demonstrates the binding affinity of <b>3c</b> for Mpro, consistent with the spectral results. Meanwhile, the binding modes and stability of thiosemicarbazone derivatives with Mpro were evaluated through molecular docking and molecular dynamics simulations, which also confirmed the stable binding between compound <b>3c</b> and Mpro. This study provides valuable insights into the interaction mechanism between thiosemicarbazone derivatives and Mpro and provides clues for the design of Mpro inhibitors.</p></div>\",\"PeriodicalId\":128,\"journal\":{\"name\":\"Archiv der Pharmazie\",\"volume\":\"358 9\",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-09-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archiv der Pharmazie\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ardp.70089\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archiv der Pharmazie","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ardp.70089","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

摘要

SARS-CoV-2大流行促使全球努力开发治疗方法。SARS-CoV-2的主要蛋白酶(Mpro)对病毒复制至关重要,也是治疗开发的关键靶点。本研究共合成了22个硫代氨基脲衍生物。酶活性测定表明,化合物3c对Mpro具有明显的抑制作用,IC50值为3.89 μM。利用同步荧光、三维荧光和圆二色光谱研究了硫代氨基脲衍生物与Mpro的相互作用机理。荧光结果表明,静态猝灭是主要的。通过微尺度热泳得到3c与Mpro之间的平衡解离常数Kd为2.3 μM。该Kd值表明3c对Mpro的结合亲和力,与光谱结果一致。同时,通过分子对接和分子动力学模拟,评价了硫代氨基脲衍生物与Mpro的结合方式和稳定性,也证实了化合物3c与Mpro的稳定结合。本研究对硫代氨基脲衍生物与Mpro的相互作用机制提供了有价值的见解,并为Mpro抑制剂的设计提供了线索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesis and Evaluation of Thiosemicarbazone Inhibitors for SARS-CoV-2 Mpro by Spectroscopy and Microscale Thermophoresis

The SARS-CoV-2 pandemic has spurred global efforts to develop therapeutic approaches. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and a key target for therapeutic development. In this study, 22 thiosemicarbazone derivatives were synthesized. Enzyme activity assays showed compound 3c exhibited obvious inhibition of Mpro, with an IC50 value of 3.89 μM. The interaction mechanisms between thiosemicarbazone derivatives and Mpro were investigated using synchronous fluorescence, three-dimensional fluorescence, and circular dichroism spectroscopy. The fluorescence results indicate that static quenching is predominant. The equilibrium dissociation constant (Kd) of 2.3 μM between 3c and Mpro was obtained by microscale thermophoresis. This Kd value demonstrates the binding affinity of 3c for Mpro, consistent with the spectral results. Meanwhile, the binding modes and stability of thiosemicarbazone derivatives with Mpro were evaluated through molecular docking and molecular dynamics simulations, which also confirmed the stable binding between compound 3c and Mpro. This study provides valuable insights into the interaction mechanism between thiosemicarbazone derivatives and Mpro and provides clues for the design of Mpro inhibitors.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信