Small-molecule modulators of PXR and CAR

•PXR and CAR are the major xenobiotic sensors that initiate detoxification.•PXR and CAR bind diverse chemical classes and exhibit species and isoform selectivity.•Crystal structures reveal the molecular basis of binding promiscuity.•Structure analysis enables prediction of modulators of PXR and CAR.•PXR and CAR are important therapeutic targets in a number of diseases.

Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating the expression of drug-metabolizing enzymes and transporters in order to degrade and excrete foreign chemicals or endogenous metabolites. This review aims to expand the perceived relevance of PXR and CAR beyond their established role as master xenosensors to disease-oriented areas, emphasizing their modulation by small molecules. Structural studies of these receptors have provided much-needed insight into the nature of their binding promiscuity and the important elements that lead to ligand binding. Reports of species- and isoform-selective activation highlight the need for further scrutiny when extrapolating from animal data to humans, as animal models are at the forefront of early drug discovery. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.