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Identification of Constitutive Androstane Receptor (CAR) Activators by Integrated Computational and Biological Approaches
Author(s) -
Lynch Caitlin,
Pan Yongmei,
Swaan Peter,
Wang Hongbing
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1014.6
Subject(s) - constitutive androstane receptor , pharmacophore , cyp2b6 , virtual screening , chemistry , computational biology , nuclear receptor , reporter gene , xenobiotic , drug metabolism , receptor , mediator , cyp3a4 , transcription factor , microbiology and biotechnology , gene , pharmacology , biology , biochemistry , cytochrome p450 , gene expression , metabolism , enzyme
The nuclear receptor CAR is a well established xenobiotic sensor governing the transcription of numerous hepatic genes associated with xenobiotic metabolism and clearance. Recent evidence suggests that mouse CAR also functions as a mediator of energy metabolism and cancer development. However, whether its human counterpart holds these novel functionsis largely unknown due to the lack of selective human (h) CAR modulators. Here, we have identified several novel hCAR activators by applying 1) virtual screening of chemical databases with ligand‐based structure‐activity models; and 2) cell‐based assays that proved to be efficient in the determination of hCAR activation. Initial screening of the CDD drug database using structure‐activity models and docking has resulted in 20 lead compounds with optimal pharmacophore parameters. In cell‐based reporter assays, two of the 20 leads exhibited robust activation of hCAR. In human primary hepatocyte cultures, these two compounds efficiently translocated hCAR from cytoplasm to nucleus, which has been recognized as the initial step of CAR activation. Moreover, these compounds also induced the expression of the prototypical hCAR target genes, CYP2B6 and CYP3A4. These results clearly indicate that our combined strategy is efficient in the identification of novel hCAR modulators. This work was partly supported by NIH Grant (DK061652).