Quantitative Structure–Activity Relationship Models with Receptor‐Dependent Descriptors for Predicting Peroxisome Proliferator‐Activated Receptor Activities of Thiazolidinedione and Oxazolidinedione Derivatives

Abstract

A quantitative structure-activity relationship study has been carried out, in which the relationship between the peroxisome proliferator-activated receptor alpha and the peroxisome proliferator-activated receptor gamma agonistic activities of thiazolidinedione and oxazolidinedione derivatives and quantitative descriptors, V(site) calculated in a receptor-dependent manner is modeled. These descriptors quantify the volume occupied by the optimized ligands in regions that are either common or specific to the superimposed binding sites of the targets under consideration. The quantitative structure-activity relationship models were built by forward stepwise linear regression modeling for a training set of 27 compounds and validated for a test set of seven compounds, resulting in a squared correlation coefficient value of 0.90 for peroxisome proliferator-activated receptor alpha and of 0.89 for peroxisome proliferator-activated receptor gamma. The leave-one-out cross-validation and test set predictability squared correlation coefficient values for these models were 0.85 and 0.62 for peroxisome proliferator-activated receptor alpha and 0.89 and 0.50 for peroxisome proliferator-activated receptor gamma respectively. A dual peroxisome proliferator-activated receptor model has also been developed, and it indicates the structural features required for the design of ligands with dual peroxisome proliferator-activated receptor activity. These quantitative structure-activity relationship models show the importance of the descriptors here introduced in the prediction and interpretation of the compounds affinity and selectivity.