Discovery and biological evaluation of cholic acid derivatives as potent TGR5 positive allosteric modulators

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2023-09-07 DOI:10.1016/j.bmc.2023.117418

Yan Li , Jingjing Sun , Xiao Wang, Zhijie Luo, Xuemei Shao, Yingxiu Li, Qirong Cao, Shuai Zhao, Mingcheng Qian, Xin Chen

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Abstract

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.

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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

本研究采用基于结构的药物设计(SBDD)方法，设计合成了22种新型胆酸(CA)衍生物，作为潜在的武田G蛋白偶联受体5 (TGR5)阳性变构调节剂(PAMs)。采用GloSensor cAMP积累法评价最终化合物的功能活性和变构机制。生物学结果表明，在cAMP形成实验中，所有目标化合物都能激活TGR5。值得注意的是，化合物B1 (CA中7-OH的选择性甲基化)对TGR5的活性比CA高5倍，并且B1正调节TGR5中鹅脱氧胆酸(CDCA)的功能活性，表明B1是TGR5的PAM。另一方面，12-羰基衍生物A1对TGR5的效价比CA高7倍。出乎意料的是，化合物A1与B1表现出相同的正变构作用，表明A1也是TGR5的PAM。分子模拟研究表明，A1中的12-羰基和B1中的12-OH与关键氨基酸Thr131形成h -键，这对TGR5的变构性能具有重要意义。综上所述，我们通过SBDD发现了两个有效的TGR5 PAMs A1和B1，它们可以作为进一步研究TGR5变构功能的先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

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.