3D QSAR studies on peroxisome proliferator-activated receptor gamma agonists using CoMFA and CoMSIA.

The peroxisome proliferator-activated receptors (PPARs) have increasingly become attractive targets for developing novel anti-type 2 diabetic drugs. We employed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to study three-dimensional quantitative structure-activity relationship (3D QSAR) based on existing agonists of PPARgamma (including five thiazolidinediones and 74 tyrosine-based compounds). Predictive 3D QSAR models with conventional r2 and cross-validated coefficient (q2) values up to 0.974 and 0.642 for CoMFA and 0.979 and 0.686 for COMSIA were established using the SYBYL package. These models were validated by a test set containing 18 compounds. The CoMFA and CoMSIA field distributions are in general agreement with the structural characteristics of the binding pockets of PPARgamma, which demonstrates that the 3D QSAR models built here are very useful in predicting activities of novel compounds for activating PPARgamma.