2. Academic Validation
  3. Highly potent non-steroidal FXR agonists protostane-type triterpenoids: Structure-activity relationship and mechanism

Highly potent non-steroidal FXR agonists protostane-type triterpenoids: Structure-activity relationship and mechanism

  • Eur J Med Chem. 2019 Nov 15;182:111652. doi: 10.1016/j.ejmech.2019.111652.
Zhi-Lin Luan 1,  Xiao-Kui Huo 1,  Pei-Pei Dong 1,  Xiang-Ge Tian 1,  Cheng-Peng Sun 2,  Xia Lv 3,  Lei Feng 1,  Jing Ning 1,  Chao Wang 1,  Bao-Jing Zhang 1,  Xiao-Chi Ma 4
Affiliations

Affiliations

  • 1 College of Pharmacy, College (Institute) of Integrative Medicine, Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, People's Republic of China.
  • 2 College of Pharmacy, College (Institute) of Integrative Medicine, Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, People's Republic of China. Electronic address: [email protected].
  • 3 Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, College of Life Science, Dalian Minzu University, Dalian, 116600, People's Republic of China.
  • 4 College of Pharmacy, College (Institute) of Integrative Medicine, Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, People's Republic of China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China. Electronic address: [email protected].
PMID: 31494470 DOI: 10.1016/j.ejmech.2019.111652
Abstract

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 (EC50 = 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.

Keywords

Farnesoid X receptor; Molecular docking; Protostane; Site-directed mutagenesis.

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