title: Discovery of new non-steroidal farnesoid X receptor modulators through 3D shape similarity search and structure-based virtual screening.
abstract: 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 3D 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 Enamine 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 IC50 values of 8.39 and 6.53 μM, respectively.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Pei
authors.initials: P
authors.lastname: Si
authors.forename: Yayun
authors.initials: Y
authors.lastname: Sheng
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Wan
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D054852:Small Molecule Libraries; D000099150:Receptor, Farnesoid X-Activated
keywords: farnesoid X receptor; modulators; similarity search; virtual screening