ArticleComputational and structural biotechnology journal2022
Discrepancy in interactions and conformational dynamics of pregnane X receptor (PXR) bound to an agonist and a novel competitive antagonist.
Article in Computational and structural biotechnology journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Recent Overview on the Molecular Hybrids Integrated With Benzosuberone/Benzo[7]annulene Derivatives as Multi-Target Therapeutics.Archiv der Pharmazie · 2026Review
- Exploring the Therapeutic Role of Pregnane X Receptor Activation in Acute Kidney Injury: Mechanisms and Clinical Implications.Current molecular medicine · 2026Review
- Mechanisms and Therapeutic Advances of PXR in Metabolic Diseases and Cancer.International journal of molecular sciences · 2025Review
- Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation.Journal of medicinal chemistry · 2025Article
- Look What You Made Me Do: Discerning Feature for Classification of Endocrine-Disrupting Chemical Binding to Steroid Hormone Receptors.Journal of chemical information and modeling · 2025Article
- The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model.Nature communications · 2025Article
- Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: AnCurrent research in toxicology · 2023Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pregnane X receptor (PXR) is a nuclear receptor with an essential role in regulating drug metabolism genes. While the mechanism of action for ligand-mediated PXR agonism is well-examined, its ligand-mediated inhibition or antagonism is poorly understood. Here we employ microsecond timescale all-atom molecular dynamics (MD) simulations to investigate how our newly identified dual kinase and PXR inhibitor, compound 100, acts as a competitive PXR antagonist and not as a full agonist. We study the PXR ligand binding domain conformational changes associated with compound 100 and compare the results to the full agonist SR12813, in presence and absence of the coactivator. Furthermore, we complement our research by experimentally disclosing the effect of eight key-residue mutations on PXR activation. Finally, simulations of P2X4 inhibitor (BAY-1797) in complex with PXR, which shares an identical structural moiety with compound 100, provide further insights to ligand-induced PXR behaviour. Our MD data suggests ligand-specific influence on conformations of different PXR-LBD regions, including α6 region, αAF-2, α1-α2', β1'-α3 and β1-β1' loop. Our results provide important insights on conformational behaviour of PXR and offers guidance how to alleviate PXR agonism or to promote PXR antagonism.
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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.