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Vol. 30, Issue 1, 96-99, January 2002
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis,
Indiana
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.
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