Abstract

The pregnane X receptor (PXR) is involved in transcriptional regulation of multiple cytochromes P450 and multidrug resistance-associated protein (MDR1), which encodes for the drug transporter P-glycoprotein. Crystal structure analyses suggest that the ligand binding domain is highly hydrophobic and flexible, allowing molecules of differing sizes to bind in multiple orientations. Using literature data for EC₅₀ (half-maximal inhibitory concentration) values for PXR activation derived for 12 human PXR ligands, a pharmacophore was developed. This pharmacophore supports the hydrophobic nature of the ligand binding domain recently deduced from the X-ray crystal structure because it contains four hydrophobic regions and one hydrogen bond acceptor. These features are consistent with at least one of the three experimentally determined orientations in which SR12813 binds to PXR, as determined by overlay studies. SR12813 fulfills all of the five pharmacophore features, as does the potent ligand hyperforin. The pharmacophore was also used to predict the binding affinity for 28 molecules not in the model but known to be PXR ligands of differing potencies. The pharmacophore distinguished the most potent activators of PXR (that display >5-fold activation/deactivation), like ecteinascidin, troglitazone, nifedipine, and dexamethasone-t-butylacetate, from poor activators, such as scopoletin and kaempferol. The model could be useful in drug development, potentially acting as a high-throughput filter for identifying compounds that may bind to PXR before in vitro determination. Ultimately, this will aid in the selection of molecules with a lesser capacity to be potent PXR ligands and thus avoid induction of numerous drug-metabolizing enzymes and MDR1.