Structural Basis for Anti-non-alcoholic Fatty Liver Disease and Diabetic Dyslipidemia Drug Saroglitazar as a PPAR α/γ Dual Agonist

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (alpha, gamma, and beta/delta) with distinct functions and PPAR dual/pan agonists are expected to be the next generation of drugs for metabolic diseases. Saroglitazar is the first clinically approved PPAR alpha/gamma dual agonist for treatment of diabetic dyslipidemia and is currently in clinical trials to treat non-alcoholic fatty liver disease (NAFLD); however, the structural information of its interaction with PPAR alpha/gamma remains unknown. We recently revealed the high-resolution co-crystal structure of saroglitazar and the PPAR alpha-ligand binding domain (LBD) through X-ray crystallography, and in this study, we report the structure of saroglitazar and the PPAR gamma-LBD. Saroglitazar was located at the center of Y-shaped PPAR gamma-ligand-binding pocket (LBP), just as it was in the respective region of PPAR alpha-LBP. Its carboxylic acid was attached to four amino acids (Ser289/His323/His449/Thr473), which contributes to the stabilization of Activating Function-2 helix 12, and its phenylpyrrole moiety was rotated 121.8 degrees in PPAR gamma-LBD from that in PPAR alpha-LBD to interact with Phe264. PPAR delta-LBD has the consensus four amino acids (Thr253/His287/His413/Tyr437) towards the carboxylic acids of its ligands, but it seems to lack sufficient space to accept saroglitazar because of the steric hindrance between the Trp228 or Arg248 residue of PPAR delta-LBD and its methylthiophenyl moiety. Accordingly, in a coactivator recruitment assay, saroglitazar activated PPAR alpha-LBD and PPAR gamma-LBD but not PPAR delta-LBD, whereas glycine substitution of either Trp228, Arg248, or both of PPARJ-LBD conferred saroglitazar concentration-dependent activation. Our findings may be valuable in the molecular design of PPAR alpha/gamma dual or PPAR alpha/gamma/delta pan agonists.

Automated summary

This study revealed the structural information of saroglitazar and its interaction with PPAR alpha and PPAR gamma, showing differences in their binding modes. The steric hindrance in PPAR gamma-LBD prevents saroglitazar binding, which has implications for the design of PPAR dual or pan agonists.