Ligand Recognition by Drug-Activated Nuclear Receptors PXR and CAR: Structural, Site-Directed Mutagenesis and Molecular Modeling Studies

Title: Ligand Recognition by Drug-Activated Nuclear Receptors PXR and CAR: Structural, Site-Directed Mutagenesis and Molecular Modeling Studies

Volume: 6 Issue: 8

Author(s): Antti Poso and Paavo Honkakoski

Affiliation:

Keywords: ligand-binding domains (LBDs), rifampicin, CYP enzymes, human PXR pharmacophore models, QSAR

Abstract: Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are the principal regulators of drug/xenobiotic disposition and toxicity. These nuclear receptors display considerable cross-regulation of their target genes, and species-specific, yet promiscuous activation by a large number of structurally dissimilar ligands. Activation of PXR and/or CAR will frequently result in enhanced drug metabolism, disturbances in homeostasis of endogenous substances, and increased toxicity. Thus, understanding, measurement and prediction of ligand-elicited activation of PXR and CAR receptors is of utmost importance for the drug development process. In this mini-review, we will review the recent elucidation of structural properties of PXR and CAR, the molecular determinants of their ligand and species specificities and progress made in in silico models for identification of PXR and CAR activators.

Cite this article as:

Poso Antti and Honkakoski Paavo, Ligand Recognition by Drug-Activated Nuclear Receptors PXR and CAR: Structural, Site-Directed Mutagenesis and Molecular Modeling Studies, Mini-Reviews in Medicinal Chemistry 2006; 6 (8) . https://dx.doi.org/10.2174/138955706777935008