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

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.

Automated summary

Cholestasis is a common clinical disease caused by a disruption in bile acids homeostasis, and the Farnesoid X receptor (FXR) plays a critical role in regulating this balance. This study aimed to identify potential FXR agonists for the treatment of cholestasis using a molecular docking-based virtual screening method. Six compounds were selected and evaluated, with licraside showing the most promising results. In vivo evaluation using an animal model confirmed that licraside reduced biliary and serum markers of cholestasis and had a therapeutic effect on liver injury. These findings highlight the potential of licraside as an FXR agonist for cholestasis treatment, and the study contributes valuable insights into the development of novel compounds from traditional Chinese medicine.