含萘-1-乙胺的 SARS-CoV-2 木瓜蛋白酶类小分子抑制剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-10-18 DOI:10.1016/j.ejmech.2024.116963

Kouki Shinohara , Takuya Kobayakawa , Kohei Tsuji , Yuki Takamatsu , Hiroaki Mitsuya , Hirokazu Tamamura

{"title":"含萘-1-乙胺的 SARS-CoV-2 木瓜蛋白酶类小分子抑制剂","authors":"Kouki Shinohara , Takuya Kobayakawa , Kohei Tsuji , Yuki Takamatsu , Hiroaki Mitsuya , Hirokazu Tamamura","doi":"10.1016/j.ejmech.2024.116963","DOIUrl":null,"url":null,"abstract":"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M<sup>pro</sup>) and a papain-like protease (PL<sup>pro</sup>), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL<sup>pro</sup> of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL<sup>pro</sup> showed that GRL-0048 noncovalently interacts with PL<sup>pro</sup>, and there is a newly identified binding pocket in PL<sup>pro</sup>. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds <strong>1</strong>, <strong>2b</strong>, and <strong>3h</strong>, that have more potent inhibitory activity than GRL-0048.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116963"},"PeriodicalIF":6.0000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2\",\"authors\":\"Kouki Shinohara , Takuya Kobayakawa , Kohei Tsuji , Yuki Takamatsu , Hiroaki Mitsuya , Hirokazu Tamamura\",\"doi\":\"10.1016/j.ejmech.2024.116963\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M<sup>pro</sup>) and a papain-like protease (PL<sup>pro</sup>), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL<sup>pro</sup> of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL<sup>pro</sup> showed that GRL-0048 noncovalently interacts with PL<sup>pro</sup>, and there is a newly identified binding pocket in PL<sup>pro</sup>. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds <strong>1</strong>, <strong>2b</strong>, and <strong>3h</strong>, that have more potent inhibitory activity than GRL-0048.</div></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"280 \",\"pages\":\"Article 116963\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0223523424008444\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523424008444","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

导致 2019 年冠状病毒病（COVID-19）的严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）尚未被根除。SARS-CoV-2 有两种蛋白酶，一种是主蛋白酶（Mpro），另一种是木瓜蛋白酶样蛋白酶（PLpro），它们共同处理两种已翻译的非结构性多聚蛋白 pp1a 和 pp1ab，生成功能性病毒蛋白。本研究以 GRL-0048 为先导，设计并合成了针对 SARS-CoV-2 PLpro 的有效抑制剂。GRL-0048与SARS-CoV-2 PLpro的对接模拟显示，GRL-0048与PLpro存在非共价相互作用，并且在PLpro中发现了一个新的结合口袋。接下来对 GRL-0048 进行了结构-活性关系研究，最终开发出了几种抑制剂，特别是化合物 1、2b 和 3h，它们比 GRL-0048 具有更强的抑制活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2

查看原文本刊更多论文

Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M^pro) and a papain-like protease (PL^pro), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL^pro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL^pro showed that GRL-0048 noncovalently interacts with PL^pro, and there is a newly identified binding pocket in PL^pro. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds 1, 2b, and 3h, that have more potent inhibitory activity than GRL-0048.

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

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.