Identification and Validation of Novel Human Pregnane X Receptor Activators among Prescribed Drugs via Ligand-Based Virtual Screening

Abstract

ABSTRACT: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 M 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 Administrationapproved and commonly prescribed drugs, which should lead to detection and prevention of potential drug-drug interactions.

Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

“…In brief, the pharmacophore protocol embedded in Discovery Studio (DS) software suite (version 3.0; Accelrys; San Diego, CA) was used to generate a qualitative CAR pharmacophore based on 17 previously reported hCAR modulators. A Bayesian model was generated based on 26-reported hCAR modulators and non-modulators (Supplementary Table S1) with protocols similar to previous publications (Pan et al , 2011; Pan et al , 2013). The model was generated with 70 physicochemical and structural descriptors including fingerprint ECFP-6 by using the “Create Bayesian Model” protocol embedded in DS 3.0 (Rogers et al , 2005).…”

“…Recent studies have demonstrated that docking and pharmacophore-based virtual screening of chemical databases combined with cell-based biological assays are effective in identifying new compounds as modulators of nuclear receptors including hCAR (Pan et al , 2011; Lynch et al , 2013). Utilizing this combined approach, here, we have retrieved 144 compounds as potential hCAR activators by virtual screening of the Specs database (www.specs.net) based on their structure-activity features.…”

Drug–Nutrient Interactions: A Broad View with Implications for Practice

“…A number of drugs (eg, amlodipine, beclomethasone, megestrol, testosterone) can activate PXR, which induces several CYP isoenzymes responsible for metabolizing many drugs and some nutrients (47,48). Other substances (eg, bergamottin found in grapefruit juice) may also influence PXR (47). As more of the substances that can activate PXR are identified, their potential involvement in drug interactions, including DNIs, can be better predicted and prevented (47).…”

“…The genetic expression of many metabolizing enzymes and some transporters is under the regulation of transcription factors such as pregnane X receptor (PXR). A number of drugs (eg, amlodipine, beclomethasone, megestrol, testosterone) can activate PXR, which induces several CYP isoenzymes responsible for metabolizing many drugs and some nutrients (47,48). Other substances (eg, bergamottin found in grapefruit juice) may also influence PXR (47).…”

“…Other substances (eg, bergamottin found in grapefruit juice) may also influence PXR (47). As more of the substances that can activate PXR are identified, their potential involvement in drug interactions, including DNIs, can be better predicted and prevented (47). As more is learned generally about specific drugs that serve as substrate, inducer, or inhibitor of various transporters and enzymes in different tissues, the more likely that direct or indirect interaction with nutrients that influence these same proteins can be determined or predicted (49).…”