Xi Lili, Shi Axi, Shen Tiantian, Wang Guoxu, Wei Yuhui, Guo Jingjing
Office of Institution of Drug Clinical Trial, The First Hospital of Lanzhou University, Lanzhou, China.
Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China.
Front Pharmacol. 2023 Jun 15;14:1197856. doi: 10.3389/fphar.2023.1197856. eCollection 2023.
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 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.
胆汁淤积是一种由胆汁酸（BAs）稳态紊乱引起的常见临床疾病，这种紊乱会促进其发展。法尼酯X受体（FXR）在调节BAs稳态中起关键作用，使其成为胆汁淤积治疗的重要靶点。尽管已经鉴定出几种活性FXR激动剂，但仍缺乏有效的胆汁淤积治疗药物。为了解决这一问题，采用了基于分子对接的虚拟筛选方法来鉴定潜在的FXR激动剂。采用分级筛选策略提高筛选准确性，选择了6种化合物进行进一步评估。使用双荧光素酶报告基因测定法证明筛选出的化合物对FXR的激活作用，然后评估其细胞毒性。在这些化合物中，licraside表现最佳，并被选择用于使用ANIT诱导的胆汁淤积动物模型进行评估。结果表明，licraside显著降低了胆汁TBA、血清ALT、AST、GGT、ALP、TBIL和TBA水平。肝脏组织病理学分析表明，licraside对ANIT诱导的肝损伤也有治疗作用。总体而言，这些发现表明licraside是一种对胆汁淤积具有潜在治疗作用的FXR激动剂。本研究为从中药中开发治疗胆汁淤积的新型先导化合物提供了有价值的见解。
