Isoform-selective modulation of peroxisome proliferator-activated receptors by quercetin and apigenin revealed through molecular simulations

This study employed an integrated computational workflow, including molecular docking, 1 µs molecular dynamics simulations, and binding free-energy calculations, to elucidate the isoform-specific interactions of the natural flavonoids apigenin and quercetin with human peroxisome proliferator-activated receptors (PPARα, PPARδ, and PPARγ). The results revealed distinct and strongly isoform-dependent interaction profiles. In PPARα, both flavonoids reduced the mobility of the activation function 2 (AF2) helix relative to the unliganded receptor, to an extent intermediate between the antagonist and the agonist, and apigenin sampled a region of the shared conformational space adjacent to that of the agonist. In PPARδ, all ligands rigidified the binding pocket to a similar degree, but apigenin alone increased the fluctuation of the AF2 helix. In PPARγ, apigenin was the only ligand that measurably increased receptor flexibility, while quercetin, the agonist, and the antagonist could not be separated on that metric. Neither flavonoid reproduced the behavior of a reference ligand across all three isoforms. Binding free-energy estimates were consistently less favorable for the flavonoids than for the reference ligands in every isoform, while physicochemical profiling indicated generally favorable drug-likeness for both compounds. Overall, these results provide a high-resolution structural framework for how apigenin and quercetin differentially engage PPAR isoforms and support testable hypotheses regarding isoform-dependent receptor modulation, without implying direct functional outcomes.