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

[ Vol. 6 , Issue. 8 ]

Author(s):

Antti Poso and Paavo Honkakoski   Pages 937 - 943 ( 7 )

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.

Keywords:

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

Affiliation:

Departments of Pharmaceutical Chemistry1 and Pharmaceutics2, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.



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