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

• DOI: 10.1124/mol.106.033415
• Publication Date: 2007-06-16T13:26:17Z
• Authors: Géraldine Lemaire; Cindy Benod; Virginie Nahoum; Arnaud Pillon; Anne-Marie Boussioux; Jean-François Gui...; Guy Subra; Jean-Marc Pascussi; William Bourguet; Alain Chavanieu; Patrick Balaguer
• Keywords: Pregnane X receptor

The human pregnane X receptor (hPXR) is a nuclear that regulates the expression of phase I and II drug-metabolizing enzymes as well drug transporters. In addition, this plays critical role in cholesterol homeostasis protecting tissues from potentially toxic endobiotics. hPXR activated by broad spectrum low-affinity compounds including xenobiotics endobiotics such bile acids their precursors. Crystallographic studies revealed ligand binding domain (LBD) with large conformable pocket likely to contribute ability respond varying size shape. Here, we describe an silico method allowed identification nine novel agonists. We further characterize compound 1-(2-chlorophenyl)-<i>N</i>-[1-(1-phenylethyl)-1<i>H</i>-benzimidazol-5-yl]methanesulfonamide (C2BA-4), methanesulfonamide activates PXR specifically more potently than does reference 4-[2,2-bis(diethoxyphosphoryl)ethenyl]-2,6-ditert-butyl-phenol (SR12813) our stable cell line expressing Gal4-PXR GAL4 driven luciferase reporter gene. Furthermore treatment primary hepatocytes C2BA-4 results marked induction mRNA target genes, cytochromes P450 3A4 2B6. Finally, also able induce hPXR-mediated vivo HGPXR bioluminescent cells implanted mice. study suggests new directions for rational design selective agonists antagonists.