title: Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking.
abstract: Farnesol X receptor (FXR) is a member of the metabolic nuclear receptor (NR) superfamily of regulatory proteins. FXR was recognized to be a transcriptional sensor for bile acids, and now it has been shown that activating FXR has important roles in controlling bile acid homeostasis, lipoprotein and glucose metabolism, and hepatic regeneration. For the sake of discovering new, potent non-steroidal FXR ligands, we have established a virtual screening workflow by using Phase Shape and induced fit docking (IFD). Phase shape was performed based on a combination of shape-only and atom types or pharmacophore modes. The results indicated that the pharmacophore mode yielded the best result for our system. The best receptor model was chosen by evaluating the cross-IFD models induced by three crystal structures 3DCT, 3FLI and 3OKI. The Enamine database was screened by the proposed workflow and 50 molecules were selected and purchased for bioassays. Among them, two compounds were found to be the new, potent FXR ligands in cell-based assay.
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: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: Pei
authors.initials: P
authors.lastname: Si
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated