Pharmacophore modeling and virtual screening studies for discovery of novel farnesoid X receptor (FXR) agonists

Farnesoid X receptor (FXR) agonists would be considered as an important therapeutic strategy for several chronic liver and metabolic diseases. Here we have employed an integrated virtual screening by combining ligand-based pharmacophore mapping and molecular docking to identify novel nonsteroidal FX...

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Bibliographic Details
Published in:RSC advances 2021-01, Vol.11 (4), p.2158-2166
Main Authors: Zhao, Shizhen, Peng, Wenjing, Li, Xinping, Wang, Le, Yin, Wenbo, Wang, Yan-Dong, Hou, Ruifang, Chen, Wei-Dong
Format: Article
Language:English
Subjects:
Assaying
Bile
Chemistry
Cholesterol
Fluorescence
Gene expression
Metabolic disorders
Molecular docking
Pharmacology
Receptors
Screening
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Summary:Farnesoid X receptor (FXR) agonists would be considered as an important therapeutic strategy for several chronic liver and metabolic diseases. Here we have employed an integrated virtual screening by combining ligand-based pharmacophore mapping and molecular docking to identify novel nonsteroidal FXR agonists. Eighteen compounds were selected for in vitro FXR agonistic activity assay, and results showed five compounds exhibiting promising FXR agonistic activity. Among these compounds, compounds F4 and F17 were the most remarkable in vitro activity by using homogeneous time resolved fluorescence (HTRF) assay and the full-length FXR reporter gene assay in HepG2 cells. Real-time PCR assay was performed to measure the expression of FXR target genes. Compounds F4 and F17 increased small heterodimer partner (SHP), in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1). The obtained compounds F4 and F17 from this study may be potential leads for developing novel FXR agonists in the treatment of metabolic diseases. In this study, we have employed an integrated virtual screening by combining ligand-based pharmacophore mapping and molecular docking to identify novel nonsteroidal FXR agonists.
ISSN:2046-2069
2046-2069
DOI:10.1039/d0ra09320c