Yan Li , Jingjing Sun , Xiao Wang, Zhijie Luo, Xuemei Shao, Yingxiu Li, Qirong Cao, Shuai Zhao, Mingcheng Qian, Xin Chen
{"title":"胆酸衍生物作为有效的TGR5阳性变构调节剂的发现和生物学评价","authors":"Yan Li , Jingjing Sun , Xiao Wang, Zhijie Luo, Xuemei Shao, Yingxiu Li, Qirong Cao, Shuai Zhao, Mingcheng Qian, Xin Chen","doi":"10.1016/j.bmc.2023.117418","DOIUrl":null,"url":null,"abstract":"<div><p>In this study, twenty-two novel cholic acid (CA) derivatives were designed and synthesized as potential Takeda G protein-coupled receptor 5 (TGR5) positive allosteric modulators (PAMs) using structure-based drug design (SBDD). GloSensor cAMP accumulation assay was employed to assess the functional activity and allosteric mechanism of final compounds. Biological results showed that all target compounds were able to activate the TGR5 in the cAMP formation assay. Remarkably, compound <strong>B1</strong>, selective methylation of 7-OH in CA, exhibited 5-fold higher activity for TGR5 compared to that of CA. Moreover, <strong>B1</strong> positively modulate the functional activity of chenodeoxycholic acid (CDCA) in TGR5, indicating that <strong>B1</strong> is a TGR5 PAM. On the other hand, 12-carbonyl derivative <strong>A1</strong> displayed 7-fold higher potency for TGR5 relative to CA. Unexpectedly, compound <strong>A1</strong> exhibited the same positive allosteric effect as <strong>B1</strong>, suggesting that <strong>A1</strong> is a TGR5 PAM as well. Molecular modeling study revealed that 12-carbonyl in <strong>A1</strong> and 12-OH in <strong>B1</strong> formed H-bolds with the key amino acid Thr131, which are significant for TGR5 allosteric property. Taken together, we found two potent TGR5 PAMs <strong>A1</strong> and <strong>B1</strong> through SBDD, which could be used as lead compounds to further study TGR5 allosteric functionality.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"92 ","pages":"Article 117418"},"PeriodicalIF":3.3000,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery and biological evaluation of cholic acid derivatives as potent TGR5 positive allosteric modulators\",\"authors\":\"Yan Li , Jingjing Sun , Xiao Wang, Zhijie Luo, Xuemei Shao, Yingxiu Li, Qirong Cao, Shuai Zhao, Mingcheng Qian, Xin Chen\",\"doi\":\"10.1016/j.bmc.2023.117418\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>In this study, twenty-two novel cholic acid (CA) derivatives were designed and synthesized as potential Takeda G protein-coupled receptor 5 (TGR5) positive allosteric modulators (PAMs) using structure-based drug design (SBDD). GloSensor cAMP accumulation assay was employed to assess the functional activity and allosteric mechanism of final compounds. Biological results showed that all target compounds were able to activate the TGR5 in the cAMP formation assay. Remarkably, compound <strong>B1</strong>, selective methylation of 7-OH in CA, exhibited 5-fold higher activity for TGR5 compared to that of CA. Moreover, <strong>B1</strong> positively modulate the functional activity of chenodeoxycholic acid (CDCA) in TGR5, indicating that <strong>B1</strong> is a TGR5 PAM. On the other hand, 12-carbonyl derivative <strong>A1</strong> displayed 7-fold higher potency for TGR5 relative to CA. Unexpectedly, compound <strong>A1</strong> exhibited the same positive allosteric effect as <strong>B1</strong>, suggesting that <strong>A1</strong> is a TGR5 PAM as well. Molecular modeling study revealed that 12-carbonyl in <strong>A1</strong> and 12-OH in <strong>B1</strong> formed H-bolds with the key amino acid Thr131, which are significant for TGR5 allosteric property. Taken together, we found two potent TGR5 PAMs <strong>A1</strong> and <strong>B1</strong> through SBDD, which could be used as lead compounds to further study TGR5 allosteric functionality.</p></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":\"92 \",\"pages\":\"Article 117418\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2023-09-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0968089623002663\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089623002663","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Discovery and biological evaluation of cholic acid derivatives as potent TGR5 positive allosteric modulators
In this study, twenty-two novel cholic acid (CA) derivatives were designed and synthesized as potential Takeda G protein-coupled receptor 5 (TGR5) positive allosteric modulators (PAMs) using structure-based drug design (SBDD). GloSensor cAMP accumulation assay was employed to assess the functional activity and allosteric mechanism of final compounds. Biological results showed that all target compounds were able to activate the TGR5 in the cAMP formation assay. Remarkably, compound B1, selective methylation of 7-OH in CA, exhibited 5-fold higher activity for TGR5 compared to that of CA. Moreover, B1 positively modulate the functional activity of chenodeoxycholic acid (CDCA) in TGR5, indicating that B1 is a TGR5 PAM. On the other hand, 12-carbonyl derivative A1 displayed 7-fold higher potency for TGR5 relative to CA. Unexpectedly, compound A1 exhibited the same positive allosteric effect as B1, suggesting that A1 is a TGR5 PAM as well. Molecular modeling study revealed that 12-carbonyl in A1 and 12-OH in B1 formed H-bolds with the key amino acid Thr131, which are significant for TGR5 allosteric property. Taken together, we found two potent TGR5 PAMs A1 and B1 through SBDD, which could be used as lead compounds to further study TGR5 allosteric functionality.
期刊介绍：
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
