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Discovery of a highly active ligand of human pregnane x receptor: a case study from pharmacophore modeling and virtual screening to "in vivo" biological activity

The human pregnane X receptor (hPXR) is a nuclear receptor that regulates the expression of phase I and II drug-metabolizing enzymes as well as that of drug transporters. In addition, this receptor plays a critical role in cholesterol homeostasis and in protecting tissues from potentially toxic endo...

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Published in:Molecular pharmacology 2007-09, Vol.72 (3), p.572-581
Main Authors: Lemaire, Géraldine, Benod, Cindy, Nahoum, Virginie, Pillon, Arnaud, Boussioux, Anne-Marie, Guichou, Jean-François, Subra, Guy, Pascussi, Jean-Marc, Bourguet, William, Chavanieu, Alain, Balaguer, Patrick
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cited_by cdi_FETCH-LOGICAL-c361t-a76c89254429c7ff74f0d4e961c3d0fd3c53bb476a7afc854eec1817a6ae7f373
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creator Lemaire, Géraldine
Benod, Cindy
Nahoum, Virginie
Pillon, Arnaud
Boussioux, Anne-Marie
Guichou, Jean-François
Subra, Guy
Pascussi, Jean-Marc
Bourguet, William
Chavanieu, Alain
Balaguer, Patrick
description The human pregnane X receptor (hPXR) is a nuclear receptor that regulates the expression of phase I and II drug-metabolizing enzymes as well as that of drug transporters. In addition, this receptor plays a critical role in cholesterol homeostasis and in protecting tissues from potentially toxic endobiotics. hPXR is activated by a broad spectrum of low-affinity compounds including xenobiotics and endobiotics such as bile acids and their precursors. Crystallographic studies revealed a ligand binding domain (LBD) with a large and conformable binding pocket that is likely to contribute to the ability of hPXR to respond to compounds of varying size and shape. Here, we describe an in silico method that allowed the identification of nine novel hPXR agonists. We further characterize the compound 1-(2-chlorophenyl)-N-[1-(1-phenylethyl)-1H-benzimidazol-5-yl]methanesulfonamide (C2BA-4), a methanesulfonamide that activates PXR specifically and more potently than does the reference compound 4-[2,2-bis(diethoxyphosphoryl)ethenyl]-2,6-ditert-butyl-phenol (SR12813) in our stable cell line expressing a Gal4-PXR and a GAL4 driven luciferase reporter gene. Furthermore treatment of primary human hepatocytes with C2BA-4 results in a marked induction of the mRNA expression of hPXR target genes, such as cytochromes P450 3A4 and 2B6. Finally, C2BA-4 is also able to induce hPXR-mediated in vivo luciferase expression in HGPXR stable bioluminescent cells implanted in mice. The study suggests new directions for the rational design of selective hPXR agonists and antagonists.
doi_str_mv 10.1124/mol.106.033415
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subjects Animals
Benzimidazoles
Benzimidazoles - pharmacology
Cell Line
Cellular Biology
Chemiluminescent Measurements
Computer Simulation
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Cytochrome P-450 Enzyme System - analysis
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - isolation & purification
Cytochrome P-450 Enzyme System - metabolism
Diphosphonates
Diphosphonates - pharmacology
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Endocrinology and metabolism
Female
Genes, Reporter
Hepatocytes
Hepatocytes - drug effects
Hepatocytes - metabolism
Human health and pathology
Humans
Life Sciences
Ligands
Luciferases
Luciferases - metabolism
Luminescent Measurements
Mice
Mice, Nude
Models, Molecular
Neoplasm Transplantation
Pharmaceutical sciences
Pregnane X Receptor
Receptors, Steroid
Receptors, Steroid - agonists
Receptors, Steroid - metabolism
RNA, Messenger
RNA, Messenger - metabolism
Structure-Activity Relationship
Sulfonamides
Sulfonamides - pharmacology
title Discovery of a highly active ligand of human pregnane x receptor: a case study from pharmacophore modeling and virtual screening to "in vivo" biological activity
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