Molecular modelling of the rat peroxisome proliferator-activated receptor -alpha (rPPARalpha) by homology with the human retinoic acid X receptor alpha (hRXRalpha) and investigation of ligand binding interactions I: QSARs.

The construction of a homology model of the ligand binding domain of the rat peroxisome proliferator-activated receptor-alpha (rPPARalpha) based on the crystal structure of the human retinoic acid X receptor-alpha (hRXRalpha) is reported. It is demonstrated that many known peroxisome proliferators are able to occupy the putative ligand binding site of the rPPARalpha, including clofibric acid, ciprofibrate, nafenopin and related compounds. The log. relative potency of several peroxisome proliferators can be quantitatively related (R=0.99) to their binding affinity and lipophilicity as measured by their distribution coefficients (logD(7.4) values) and other QSARs are discussed in the light of receptor-ligand interactions. The molecular modelling of a representative number of peroxisome proliferators within the putative ligand binding site is consistent with experimental information on relative potency and enantioselectivity.