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| - The Identification of Ligand Features Essential for PXR Activation by PharmacophoreModeling
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| - Drug metabolizing enzymes and transporters are often involved in clinically relevant drug-drug interactions.These functional proteins can be induced by a wide range of xenobiotics. The induction is mediated by agroup of receptors known as orphan nuclear receptors. The pregnane X receptor (PXR) is a member of thisreceptor family and regulates the expression of multiple Cytochrome P450 enzyme families (e.g. CYP 3Aand 2B), phase II enzymes (e.g. UDP glucuronosyl transferases), and transporters (e.g. multidrug resistanceprotein 1). The software package Catalyst was employed to derive pharmacophore models for PXR activation.A structure based pharmacophore hypothesis and several ligand based ones were compared in order toidentify ligand receptor interactions essential for receptor activation. The results suggest that hydrogen bondingto Gln285 is indispensable for PXR activation. Most ligands were found to form a second hydrogen bondto His407. Hydrophobic interactions are not essential for receptor activation but contribute to ligand affinity.Highly active compounds share up to five hydrophobic features that allow the ligand to occupy large areasof the predominantly hydrophobic binding pocket.
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