Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies

Author:

Xi Lili,Shi Axi,Shen Tiantian,Wang Guoxu,Wei Yuhui,Guo Jingjing

Abstract

Cholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agonists have been identified, effective drugs for cholestasis are still lacking. To address this, a molecular docking-based virtual screening method was used to identify potential FXR agonists. A hierarchical screening strategy was employed to improve the screening accuracy, and six compounds were selected for further evaluation. Dual-luciferase reporter gene assay was used to demonstrate FXR activation by the screened compounds, and their cytotoxicity was then evaluated. Among the compounds, licraside showed the best performance and was selected for in vivo evaluation using an ANIT-induced cholestasis animal model. Results demonstrated that licraside significantly reduced biliary TBA, serum ALT, AST, GGT, ALP, TBIL, and TBA levels. Liver histopathological analysis showed that licraside also had a therapeutic effect on ANIT-induced liver injury. Overall, these findings suggest that licraside is an FXR agonist with potential therapeutic effects on cholestasis. This study provides valuable insights into the development of novel lead compounds from traditional Chinese medicine for cholestasis treatment.

Funder

National Natural Science Foundation of China

Publisher

Frontiers Media SA

Subject

Pharmacology (medical),Pharmacology

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets;Signal Transduction and Targeted Therapy;2024-04-26

2. Targeting bile salt homeostasis in biliary diseases;Current Opinion in Gastroenterology;2024-01-10

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