RT Journal Article SR Electronic T1 Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 337 OP 344 DO 10.1124/dmd.110.035808 VO 39 IS 2 A1 Yongmei Pan A1 Linhao Li A1 Gregory Kim A1 Sean Ekins A1 Hongbing Wang A1 Peter W. Swaan YR 2011 UL http://dmd.aspetjournals.org/content/39/2/337.abstract AB Human pregnane X receptor (hPXR) plays a key role in regulating metabolism and clearance of endogenous and exogenous substances. Identification of novel hPXR activators among commercial drugs may aid in avoiding drug-drug interactions during coadministration. We applied ligand-based computational approaches for virtual screening of a commonly prescribed drug database (SCUT). Bayesian classification models were generated with a training set comprising 177 compounds using Fingerprints and 117 structural descriptors. A cell-based luciferase reporter assay was used for evaluation of chemical-mediated hPXR activation in HepG2 cells. All compounds were tested at 10 μM concentration with rifampicin and dimethyl sulfoxide as positive and negative controls, respectively. The Bayesian models showed specificity and overall prediction accuracy up to 0.92 and 0.69 for test set compounds. Screening the SCUT database with this model retrieved 105 hits and 17 compounds from the top 25 hits were chosen for in vitro testing. The reporter assay confirmed that nine drugs, i.e., fluticasone, nimodipine, nisoldipine, beclomethasone, finasteride, flunisolide, megestrol, secobarbital, and aminoglutethimide, were previously unidentified hPXR activators. Thus, the present study demonstrates that novel hPXR activators can be efficiently identified among U.S. Food and Drug Administration-approved and commonly prescribed drugs, which should lead to detection and prevention of potential drug-drug interactions.