Licraside 作为缓解胆汁淤积的新型有效 FXR 激动剂：基于结构的药物发现和生物学评价研究,Frontiers in Pharmacology

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Licraside 作为缓解胆汁淤积的新型有效 FXR 激动剂：基于结构的药物发现和生物学评价研究
Frontiers in Pharmacology ( IF 4.4 ) Pub Date : 2023-06-15 , DOI: 10.3389/fphar.2023.1197856
Lili Xi ₁ , Axi Shi ₂ , Tiantian Shen ₃ , Guoxu Wang ₄ , Yuhui Wei ₂ , Jingjing Guo ₅

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胆汁淤积是临床常见疾病，由胆汁酸（BA）稳态紊乱引起，并促进其发生发展。Farnesoid X 受体 (FXR) 在调节 BA 稳态中发挥着关键作用，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，但仍然缺乏有效的胆汁淤积药物。为了解决这个问题，使用基于分子对接的虚拟筛选方法来识别潜在的 FXR 激动剂。采用分层筛选策略来提高筛选准确性，并选择六种化合物进行进一步评估。使用双荧光素酶报告基因测定来证明筛选的化合物对 FXR 的激活，然后评估其细胞毒性。在这些化合物中，利卡苷表现出最好的性能，并被选为体内使用 ANIT 诱导的胆汁淤积动物模型进行评估。结果表明，利卡苷显着降低胆汁 TBA、血清 ALT、AST、GGT、ALP、TBIL 和 TBA 水平。肝脏组织病理学分析显示利卡苷对ANIT所致的肝损伤也有治疗作用。总体而言，这些研究结果表明利卡苷是一种 FXR 激动剂，对胆汁淤积具有潜在的治疗作用。这项研究为开发用于治疗胆汁淤积的新型中药先导化合物提供了宝贵的见解。

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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.

更新日期：2023-06-15

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