ArticleDrug metabolism and disposition: the biological fate of chemicals2011
Identification and validation of novel human pregnane X receptor activators among prescribed drugs via ligand-based virtual screening.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 42 citations in OpenAlex.
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- Thiazide-like diuretic drug metolazone activates human pregnane X receptor to induce cytochrome 3A4 and multidrug-resistance protein 1.Biochemical pharmacology · 2014Article
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- Fusing dual-event data sets for Mycobacterium tuberculosis machine learning models and their evaluation.Journal of chemical information and modeling · 2013Article
- Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery.Bioorganic & medicinal chemistry · 2013Article
- Modulation of xenobiotic receptors by steroids.Molecules (Basel, Switzerland) · 2013Review
- Pharmacophore and 3D-QSAR characterization of 6-arylquinazolin-4-amines as Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitors.Journal of chemical information and modeling · 2013Article
- Identification of novel activators of constitutive androstane receptor from FDA-approved drugs by integrated computational and biological approaches.Pharmaceutical research · 2013Article
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 1 institution in 1 country.
Funding
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 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.