Crystal structure of the peroxisome proliferator-activated receptor γ (PPARγ) ligand binding domain complexed with a novel partial agonist: A new region of the hydrophobic pocket could be exploited for drug design

The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating glucose and lipid metabolism. The search for new PPAR ligands with reduced adverse effects with respect to the marketed antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is highly desired. We report the crystal structure and activity of the two enantiomeric forms of a clofibric acid analogue, respectively complexed with the ligand-binding domain (LBD) of PPARγ, and provide an explanation on a molecular basis for their different potency and efficacy against PPARγ. The more potent S-enantiomer is a dual PPARα/PPARγ agonist which presents a partial agonism profile against PPARγ. Docking of the S-enantiomer in the PPARα-LBD has been performed to explain its different subtype pharmacological profile. The hypothesis that partial agonists show differential stabilization of helix 3, when compared to full agonists, is also discussed. Moreover, the structure of the complex with the S-enantiomer reveals a new region of the PPARγ-LBD never sampled before by other ligands. © 2008 American Chemical Society.