The identification of ligand features essential for PXR activation by pharmacophore modeling

@article{citeulike:2103252, abstract = {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 inediated by a group of receptors known as orphan nuclear receptors. The pregnane X receptor (PXR) is a member of this receptor family and regulates the expression of multiple Cytochrome P450 enzyme families (e.g. CYP 3A and 213), phase II enzymes (e.g. UDP glucuronosyl transferases), and transporters (e.g. multidrug resistance protein 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 to identify ligand receptor interactions essential for receptor activation. The results suggest that hydrogen bonding to Gln285 is indispensable for PXR activation. Most ligands were found to form a second hydrogen bond to His407. Hydrophobic interactions are not essential for receptor activation but Contribute to ligand affinity. Highly active compounds share LIP to five hydrophobic features that allow the ligand to Occupy large areas of the predominantly hydrophobic binding pocket. [References: 24]}, author = {Schuster, D. and Langer, T. }, citeulike-article-id = {2103252}, journal = {Journal of Chemical Information \& Modeling}, keywords = {induction, p450, pxr}, number = {2}, pages = {431--439}, posted-at = {2008-05-27 12:55:43}, priority = {2}, title = {The identification of ligand features essential for PXR activation by pharmacophore modeling}, volume = {45}, year = {2005} }

TY - JOUR ID - citeulike:2103252 L3 - citeulike-article-id:2103252 N2 - 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 inediated by a group of receptors known as orphan nuclear receptors. The pregnane X receptor (PXR) is a member of this receptor family and regulates the expression of multiple Cytochrome P450 enzyme families (e.g. CYP 3A and 213), phase II enzymes (e.g. UDP glucuronosyl transferases), and transporters (e.g. multidrug resistance protein 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 to identify ligand receptor interactions essential for receptor activation. The results suggest that hydrogen bonding to Gln285 is indispensable for PXR activation. Most ligands were found to form a second hydrogen bond to His407. Hydrophobic interactions are not essential for receptor activation but Contribute to ligand affinity. Highly active compounds share LIP to five hydrophobic features that allow the ligand to Occupy large areas of the predominantly hydrophobic binding pocket. [References: 24] IS - 2 JF - Journal of Chemical Information \& Modeling EP - 439 TI - The identification of ligand features essential for PXR activation by pharmacophore modeling VL - 45 SP - 431 KW - induction KW - p450 KW - pxr AU - Schuster, D AU - Langer, T PY - 2005/// ER -