Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking

Discovery of two new, potent FXR ligands by ligand- and receptor-based methods. 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-11, Vol.22 (22), p.6848-6853
Main Authors: Fu, Jing, Si, Pei, Zheng, Mingyue, Chen, Lili, Shen, Xu, Tang, Yun, Li, Weihua
Format: Article
Language:English
Subjects:
bile acids
Binding Sites
bioassays
Biological and medical sciences
crystal structure
Databases, Chemical
Docking
Drug Evaluation, Preclinical
farnesol
FXR
glucose
homeostasis
Hydrogen Bonding
Ligands
lipoproteins
Medical sciences
metabolism
Molecular Docking Simulation
pharmacology
Pharmacology. Drug treatments
Phase shape
Protein Structure, Tertiary
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear - metabolism
regulatory proteins
screening
transcription (genetics)
Virtual screening
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Summary:Discovery of two new, potent FXR ligands by ligand- and receptor-based methods. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.09.045