College of Pharmacy, College (Institute) of Integrative Medicine, Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, People's Republic of China.
College of Pharmacy, College (Institute) of Integrative Medicine, Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, People's Republic of China.
Eur J Med Chem. 2019 Nov 15;182:111652. doi: 10.1016/j.ejmech.2019.111652. Epub 2019 Aug 28.
Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1-14) and four known analogues (15-18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1-70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology.
法尼醇 X 受体（FXR）是负责胆汁酸合成、转运和代谢的关键调节因子。FXR 的激活抑制胆汁酸的合成，增加其排泄和转运，从而保护肝功能。因此，FXR 被认为是胆汁淤积和非酒精性脂肪性肝炎的重要治疗靶点。本文从泽泻中分离鉴定了 14 个新的原甾烷型三萜（1-14）和 4 个已知类似物（15-18），并最终构建了一个原甾烷型三萜小分子库（1-70），以研究其与 FXR 的构效关系，进一步得到具有强 FXR 激动活性的化合物 15（EC50=90nM）。体外实验证实了化合物 15 对 FXR 的高效作用，并通过分子对接和定点突变技术揭示了其 FXR 激活的潜在机制（氨基酸残基 Arg331 和 Ser332）。
