Insights into ligand-elicited activation of human constitutive androstane receptor based on novel agonists and three-dimensional quantitative structure-activity relationship.

The human constitutive androstane receptor (CAR, NR1I3) is an important regulator of xenobiotic metabolism and other physiological processes. So far, only few CAR agonists are known and no explicit mechanism has been proposed for their action. Thus, we aimed to generate a 3D QSAR model that could explain the molecular determinants of CAR agonist action. To obtain a sufficient number of agonists that cover a wide range of activity, we applied a virtual screening approach using both structure- and ligand-based methods. We identified 27 novel human CAR agonists on which a 3D QSAR model was generated. The model, complemented by coregulator recruitment and mutagenesis results, suggests a potential activation mechanism for human CAR and may serve to predict potential activation of CAR for compounds emerging from drug development projects or for chemicals undergoing toxicological risk assessment.