Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.
Sarah A MosureJinsai ShangJerome EberhardtRichard BrustJie ZhengPatrick R GriffinStefano ForliDouglas J KojetinPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- insulin resistance
- molecular docking
- type diabetes
- mass spectrometry
- drug administration
- fatty acid
- structural basis
- gene expression
- high resolution
- atrial fibrillation
- single cell
- cardiovascular disease
- high throughput
- magnetic resonance
- skeletal muscle
- risk assessment
- drug induced
- oxidative stress
- climate change
- nuclear factor
- toll like receptor
- glycemic control
- data analysis