溴邻苯二酚-查尔酮衍生物对 PTP1B 的异位抑制作用

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-13 DOI:10.1016/j.ejmech.2024.117053

Chenxia Gao, Wenpeng Hu, Feng Xu, Yuxi Lin, Jiashu Chen, Dayong Shi, Pan Xing, Jiqiang Zhu, Xiangqian Li

{"title":"溴邻苯二酚-查尔酮衍生物对 PTP1B 的异位抑制作用","authors":"Chenxia Gao, Wenpeng Hu, Feng Xu, Yuxi Lin, Jiashu Chen, Dayong Shi, Pan Xing, Jiqiang Zhu, Xiangqian Li","doi":"10.1016/j.ejmech.2024.117053","DOIUrl":null,"url":null,"abstract":"Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC50 value of 1.061±0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"216 1","pages":""},"PeriodicalIF":6.0000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives\",\"authors\":\"Chenxia Gao, Wenpeng Hu, Feng Xu, Yuxi Lin, Jiashu Chen, Dayong Shi, Pan Xing, Jiqiang Zhu, Xiangqian Li\",\"doi\":\"10.1016/j.ejmech.2024.117053\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC50 value of 1.061±0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"216 1\",\"pages\":\"\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-11-13\",\"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://doi.org/10.1016/j.ejmech.2024.117053\",\"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://doi.org/10.1016/j.ejmech.2024.117053","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

开发异构抑制剂可能是发现针对 PTP1B 的降糖药物的可行策略。异构抑制剂占据的 BB 位点是一个疏水口袋，它限制了处于开放构象的 WPD 环，从而阻止了生理上的去磷酸化反应。针对 BB 位点，研究人员设计并合成了 60 种溴邻苯二酚-查尔酮衍生物，作为 PTP1B 的异构抑制剂，以防治糖尿病。最有效的化合物 LXQ-87（C8）对 PTP1B 具有非竞争性抑制作用，IC50 值为 1.061±0.202 μM。口服 LXQ-87 可降低 BKS db/db T2DM 小鼠的空腹血糖水平，改善糖耐量和血脂异常。LXQ-87 通过直接与细胞内的 PTP1B 结合，缓解了胰岛素抵抗，促进了细胞的葡萄糖摄取。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

查看原文本刊更多论文

Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC₅₀ value of 1.061±0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.

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.