Molecular modeling study of species-selective peroxisome proliferator-activated receptor (PPAR) alpha agonist; possible mechanism(s) of human PPARalpha selectivity of an alpha-substituted phenylpropanoic acid derivative (KCL).

In order to investigate the reason why phenylpropanoic acid derivative (KCL), a potent, human peroxisome proliferator-activated receptor (PPAR) alpha-selective agonist, shows this selectivity, we analyzed the binding modes of KCL and a related compound to the ligand-binding domain of human PPARalpha and rat PPARalpha by means of computer-aided molecular modeling. We concluded that the characteristic specificity of KCL is due to a specific hydrophobic contact between the hydrophobic tail part (the 4-trifluoromethyl group) and the key amino acid Ile272 located on the helix three region of the human PPARalpha ligand binding domain. We propose a possible binding mode of KCL with the ligand-binding domain of human PPARalpha. This binding model should offer important insights for further structural design of subtype-selective PPARalpha agonists for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.