ArticleBiochemical pharmacology2013
Differential regulation of CYP3A4 promoter activity by a new class of natural product derivatives binding to pregnane X receptor.
Article in Biochemical pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- Enterococcus hirae Y-HS Alleviates Ulcerative Colitis by Activating PXR/Nrf2-mediated Metabolic-immune Crosstalk.Probiotics and antimicrobial proteins · 2026Article
- Transcription Factors and ncRNAs Associated withBiomedicines · 2022Article
- Article
- Why We Need to Take a Closer Look at Genetic Contributions to CYP3A Activity.Frontiers in pharmacology · 2022Review
- Discrepancy in interactions and conformational dynamics of pregnane X receptor (PXR) bound to an agonist and a novel competitive antagonist.Computational and structural biotechnology journal · 2022Article
- The Role of Vitamin K in Cholestatic Liver Disease.Nutrients · 2021Review
- Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning.Cellular and molecular life sciences : CMLS · 2021Article
- PXR is a target of (-)-epicatechin in skeletal muscle.Heliyon · 2020Article
- Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor.Journal of medicinal chemistry · 2020Article
- Drug discovery technologies to identify and characterize modulators of the pregnane X receptor and the constitutive androstane receptor.Drug discovery today · 2019Review
- Exploring the PXR ligand binding mechanism with advanced Molecular Dynamics methods.Scientific reports · 2018Article
- Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery.Current drug metabolism · 2017Review
- Tryptophan 299 is a conserved residue of human pregnane X receptor critical for the functional consequence of ligand binding.Biochemical pharmacology · 2016Article
- Targeting xenobiotic receptors PXR and CAR in human diseases.Drug discovery today · 2015Review
- Thiazide-like diuretic drug metolazone activates human pregnane X receptor to induce cytochrome 3A4 and multidrug-resistance protein 1.Biochemical pharmacology · 2014Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The pregnane X receptor (PXR) regulates drug metabolism by regulating the expression of drug-metabolizing enzymes such as cytochrome P450 3A4 (CYP3A4), which is involved in the metabolism of >50% of clinically prescribed drugs. The activity of PXR can be controlled by the binding of small molecule agonists or antagonists. Because of its unique ligand binding pocket, PXR binds promiscuously to structurally diverse chemicals. To study the structure-activity relationship, novel modulators for PXR are needed. Here we report the virtual screening of ∼25,000 natural product derivatives from the ZINC database using the Molecular Operating Environment docking software tool against the PXR-rifampicin complex X-ray crystal structure. Our screening resulted in identification of compounds based on the lowest S score, which measures Gibbs free energy. Interestingly, we found that the compounds that bind directly to PXR, as revealed in an intrinsic tryptophan fluorescence assay, modulate CYP3A4 promoter activity differentially in HepG2 cells. Mutational analysis and docking studies showed that these compounds bind broadly in the ligand binding pocket but interact with different amino acid residues. We further investigated the mechanism of binding by analyzing the functional groups that are important for distinguishing agonists from antagonists. The approach we used to identify novel modulators that bind to PXR can be useful for finding novel modulators of PXR.
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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.