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Discovery of New Non‐Steroidal F arnesoid X R eceptor Modulators Through 3 D Shape Similarity Search and Structure‐Based Virtual Screening
Author(s) -
Wang Lei,
Si Pei,
Sheng Yayun,
Chen Yingjie,
Wan Ping,
Shen Xu,
Tang Yun,
Chen Lili,
Li Weihua
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12432
Subject(s) - farnesoid x receptor , virtual screening , docking (animal) , chemistry , structural similarity , ligand (biochemistry) , biochemistry , receptor , bioassay , computational biology , transcription factor , small molecule , stereochemistry , nuclear receptor , biology , drug discovery , genetics , gene , medicine , nursing
As a ligand‐activated transcriptional factor, farnesoid X receptor ( FXR ) has a variety of biological functions, such as biosynthesis of bile acids, metabolism of lipid, and glucose homeostasis, and thus is related to multiple diseases, especially metabolic syndrome. In this study, to discover new FXR modulators, we have designed a strategy by combining 3 D shape similarity search and structure‐based docking methods. Taking two FXR ligands that we previously reported as the reference molecules, virtual screening was performed against the E namine database, and finally 59 compounds were selected for bioassay. Among them, four compounds exhibited agonistic or antagonistic activities against FXR in homogeneous time resolved fluorescence assay. Two of them were found to be new, potent FXR antagonists in cell‐based assay with IC 50 values of 8.39 and 6.53 μ m , respectively.