Structure-based drug design of a novel family of PPARγ partial agonists: Virtual screening, X-ray crystallography, and in vitro/in vivo biological activities

Peroxisome proliferator-activated receptor γ (PPARγ) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARγ agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARγ and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARγ. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARγ could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARα and PPARδ, and steric hindrance upon the ligand binding.