title: Identification of novel activators of constitutive androstane receptor from FDA-approved drugs by integrated computational and biological approaches.
abstract: OBJECTIVE
  The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic sensor governing the transcription of numerous hepatic genes associated with drug metabolism and clearance. Recent evidence suggests that CAR also modulates energy homeostasis and cancer development. Thus, identification of novel human (h) CAR activators is of both clinical importance and scientific interest.
  
  
  METHODS
  Docking and ligand-based structure-activity models were used for virtual screening of a database containing over 2000 FDA-approved drugs. Identified lead compounds were evaluated in cell-based reporter assays to determine hCAR activation. Potential activators were further tested in human primary hepatocytes (HPHs) for the expression of the prototypical hCAR target gene CYP2B6.
  
  
  RESULTS
  Nineteen lead compounds with optimal modeling parameters were selected for biological evaluation. Seven of the 19 leads exhibited moderate to potent activation of hCAR. Five out of the seven compounds translocated hCAR from the cytoplasm to the nucleus of HPHs in a concentration-dependent manner. These compounds also induce the expression of CYP2B6 in HPHs with rank-order of efficacies closely resembling that of hCAR activation.
  
  
  CONCLUSIONS
  These results indicate that our strategically integrated approaches are effective in the identification of novel hCAR modulators, which may function as valuable research tools or potential therapeutic molecules.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn. Street, Baltimore, Maryland 21201, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Lynch
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Pan
authors.forename: Linhao
authors.initials: L
authors.lastname: Li
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Ferguson
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Peter W
authors.initials: PW
authors.lastname: Swaan
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000737:chemistry; D010600:Pharmacology; D021381:Protein Transport / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D004364:Pharmaceutical Preparations; D018160:Receptors, Cytoplasmic and Nuclear; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating