PPARα and δ Ligand Design: Honing the Traditional Empirical Method with a More Holistic Overview

Peroxisome proliferator-activated receptor (PPAR) ligands have been used in clinical therapy to treat metabolic disease since the 1960s. However, these ligands have side effects that restrict their use, thought to be caused, in part, by their broad specificity. Efforts have been made to synthesize new ligands; however, most have failed to pass clinical trials. Here we examine the available crystal structures of PPAR in complex with ligands to identify common ligand design factors for selectivity towards a PPAR subtype. Methods to improve drug-lead identification and optimization and other factors that may contribute to design of a successful PPAR ligand are discussed.