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Novel ligands for human pregnane X receptor differentially regulate CYP3A4 promoter activity (579.1)
Author(s) -
Banerjee Monimoy,
Chen Taosheng
Publication year - 2014
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.28.1_supplement.579.1
Subject(s) - pregnane x receptor , nuclear receptor , cyp3a4 , constitutive androstane receptor , chemistry , docking (animal) , pregnane , regulator , cytochrome p450 , receptor , drug metabolism , biochemistry , binding site , ligand (biochemistry) , pharmacology , metabolism , biology , transcription factor , stereochemistry , gene , medicine , nursing
Human pregnane X receptor (hPXR) also known as xenobiotic sensing nuclear receptor (SXR) is a member of nuclear receptor family and a critical regulator of the expression of genes involved in drug metabolism and clearance. The pregnane X receptor (PXR) regulates drug metabolism by regulating the expression of drug‐metabolizing enzymes such as cytochrome P450 3A4 (CYP3A4), which is involved in the metabolism of >50% of clinically prescribed drugs. It also plays an important role in cancer drug resistance by regulating the expression of MDR1. Activity of PXR can be modulated by agonists or antagonists. There are several agonists for PXR have been reported but the reported antagonists for PXR are limited. Therefore, there is still need to develop novel ligands for PXR. Here, we report the virtual screening of ~25,000 natural product derivatives from the ZINC database using the MOE docking software tool against the PXR‐Rifampicin complex X‐ray crystal structure. Our screening resulted in identification of compounds based on the lowest S scores which measures binding energy. All of these ligands were docked within the ligand binding pocket forming interactions with several hydrophobic amino acid residues. Further, all these main compounds and analogs were synthesized to verify with biological assays. We found that the compounds that bind directly to PXR, as revealed in an intrinsic tryptophan fluorescence assay, modulate CYP3A4 promoter activity differentially in HepG2 cells. Mutational analysis and docking studies showed that these compounds bind broadly in the ligand binding pocket but interact with different amino acid residues. The mechanism of binding and the functional group of the ligands that are important for distinguishing agonists/antagonists were also investigated. Grant Funding Source : Supported by the ALSAC, St. Jude CRH, NIH, NCI.