TY - JOUR T1 - In Silico Prediction of Pregnane X Receptor Activators by Machine Learning Approache JF - Molecular Pharmacology JO - Mol Pharmacol SP - 158 LP - 168 DO - 10.1124/mol.106.027623 VL - 71 IS - 1 AU - C. Y. Ung AU - H. Li AU - C. W. Yap AU - Y. Z. Chen Y1 - 2007/01/01 UR - http://molpharm.aspetjournals.org/content/71/1/158.abstract N2 - Pregnane X receptor (PXR) regulates drug metabolism and is involved in drug-drug interactions. Prediction of PXR activators is important for evaluating drug metabolism and toxicity. Computational pharmacophore and quantitative structure-activity relationship models have been developed for predicting PXR activators. Because of the structural diversity of PXR activators, more efforts are needed for exploring methods applicable to a broader spectrum of compounds. We explored three machine learning methods (MLMs) for predicting PXR activators, which were trained and tested by using significantly higher number of compounds, 128 PXR activators (98 human) and 77 PXR non-activators, than those of previous studies. The recursive feature-selection method was used to select molecular descriptors relevant to PXR activator prediction, which are consistent with conclusions from other computational and structural studies. In a 10-fold cross-validation test, our MLM systems correctly predicted 81.2 to 84.0% of PXR activators, 80.8 to 85.0% of hPXR activators, 61.2 to 70.3% of PXR nonactivators, and 67.7 to 73.6% of hPXR nonactivators. Our systems also correctly predicted 73.3 to 86.7% of 15 newly published hPXR activators. MLMs seem to be useful for predicting PXR activators and for providing clues to physicochemical features of PXR activation. The American Society for Pharmacology and Experimental Therapeutics ER -