Discovery of novel cholic acid derivatives as highly potent agonists for G protein-coupled bile acid receptor

Mingcheng Qian; Zhijie Luo; Wenwen Hou; Jingjing Sun; Xin Lu; Qianxi Zhang; Yi Wu; Caile Xue; Shuai Zhao; Xin Chen

doi:10.1016/j.bioorg.2021.105588

Discovery of novel cholic acid derivatives as highly potent agonists for G protein-coupled bile acid receptor

Bioorg Chem. 2022 Mar:120:105588. doi: 10.1016/j.bioorg.2021.105588. Epub 2021 Dec 30.

Authors

Mingcheng Qian¹, Zhijie Luo¹, Wenwen Hou¹, Jingjing Sun¹, Xin Lu¹, Qianxi Zhang¹, Yi Wu¹, Caile Xue¹, Shuai Zhao¹, Xin Chen²

Affiliations

¹ School of Pharmacy, Changzhou University, Changzhou 213164, PR China.
² School of Pharmacy, Changzhou University, Changzhou 213164, PR China. Electronic address: xinchen@cczu.edu.cn.

PMID: 34979448
DOI: 10.1016/j.bioorg.2021.105588

Abstract

In this study, fourteen new cholic acid (CA) derivatives were designed and synthesized, and the GloSensor cAMP accumulation assay indicated that all derivatives could activate the Takeda G protein-coupled receptor 5 (TGR5). Methylation of 7- and 12-hydroxyl groups in CA significantly increased TGR5 agonism for the new derivatives. For example, 7,12-dimethoxy derivative B1 exhibited 78-fold higher potency for TGR5 than the 7,12-dihydroxyl derivative A1 and 258-fold higher potency than CA itself. On the other hand, A1 positively modulated chenodeoxycholic acid (CDCA) functional activity in TGR5, whereas B1 did not show similar activity. Molecular docking experiments indicated that A1 formed a hydrogen bond between the 12-OH and amino acid Thr131 of TGR5, which is significant for its allosteric property. However, methylation at the 12-hydroxyl group in CA (derivative B1) disrupted this pivotal H-bond. Therefore, the free 12-hydroxyl group is essential for the CA derivatives in TGR5 allosteric agonism. Overall, we discovered a highly potent TGR5 agonist, B1, which can be used as lead compound for further study.

Keywords: Agonists; Cholic acid; G protein-coupled bile acid receptor 1; Receptor allostery; Takeda G protein-coupled receptor 5.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Acids and Salts*
Cholic Acid / pharmacology
GTP-Binding Proteins / metabolism
Molecular Docking Simulation
Receptors, G-Protein-Coupled* / metabolism

Substances

Bile Acids and Salts
Receptors, G-Protein-Coupled
GTP-Binding Proteins
Cholic Acid