Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies.
Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies.
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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。
DOI：
10.3389/fphar.2023.1197856
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
胆汁淤积症是胆汁酸体内平衡紊乱引起的临床常见病，胆汁淤积症的发生是由胆汁淤积症引起的。Farnesoid X受体（FXR）在调节BAs稳态中起关键作用，使其成为治疗胆汁淤积症的重要靶点。虽然已经发现了几种有效的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。为了提高筛选的准确性，采用了分级筛选策略，并筛选出6个化合物进行进一步评价。采用双荧光素酶报告基因法验证筛选的化合物对FXR的激活作用，并对其细胞毒性进行评价。在这些化合物中，地衣皂苷表现出最好的性能，并被选中进行体内评价，使用anit诱导的胆汁淤积动物模型。结果表明，甘草皂苷可显著降低胆汁TBA、血清ALT、AST、GGT、ALP、TBIL和TBA水平。肝组织病理学分析表明，甘草皂苷对anit诱导的肝损伤也有治疗作用。总的来说，这些发现表明，licraside是一种FXR激动剂，对胆汁淤积有潜在的治疗作用。本研究为开发治疗胆汁淤积症的新型中药先导化合物提供了有价值的见解。
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.
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DOI：
10.1002/hep.27744
发表时间：
2015-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ghonem NS;Assis DN;Boyer JL
通讯作者：
Boyer JL
影响因子：
3.9
作者：
Stofan M;Guo GL
通讯作者：
Guo GL
DOI：
10.1016/j.apsb.2015.01.004
发表时间：
2015-03
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Ding L;Yang L;Wang Z;Huang W
通讯作者：
Huang W
影响因子：
13.5
作者：
Kong, Bo;Wang, Li;Guo, Grace L.
通讯作者：
Guo, Grace L.
影响因子：
--
作者：
Santiago, Priscila;Levy, Cynthia
通讯作者：
Levy, Cynthia