ArticleJournal of medicinal chemistry2019
Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.
Article in Journal of medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 35 citations in OpenAlex.
- Unlocking the potential of mRNA nanomedicines for comprehensive fibrosis therapy.Molecular therapy. Nucleic acids · 2026Review
- PPARγ activation ameliorates cognitive impairment and chronic microglial activation in the aftermath of r-mTBI.Journal of neuroinflammation · 2024Article
- VSP-2 attenuates secretion of inflammatory cytokines induced by LPS in BV2 cells by mediating the PPARγOpen life sciences · 2024Article
- Novel Derivatives of Eugenol as a New Class of PPARγ Agonists in Treating Inflammation: Design, Synthesis, SAR Analysis and In Vitro Anti-Inflammatory Activity.Molecules (Basel, Switzerland) · 2023Article
- Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate.International journal of molecular sciences · 2023Review
- Novel derivatives of eugenol as potent anti-inflammatory agentsRSC advances · 2022Article
- Nanostructured Lipid Carrier-Based Delivery of Pioglitazone for Treatment of Type 2 Diabetes.Frontiers in pharmacology · 2022Article
- Structural mechanism underlying ligand binding and activation of PPARγ.Structure (London, England : 1993) · 2021Article
- Ectopic Overexpression of PPARγ2 in the Heart Determines Differences in Hypertrophic Cardiomyopathy After Treatment With Different Thiazolidinediones in a Mouse Model of Diabetes.Frontiers in pharmacology · 2021Article
- Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations.International journal of molecular sciences · 2020Article
- Quantitative structural assessment of graded receptor agonism.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
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Registered trials
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.