Quantitative structure-activity relationship (QSAR) studies for predicting activation of the ryanodine receptor type 1 channel complex (RyR1) by polychlorinated biphenyl (PCB) congeners

Abstract

A quantitative structure-activity relationship (QSAR) was developed to predict the congener specific ryanodine receptor type RyR1 activity of all 209 polychlorinated biphenyl (PCB) congeners. A three-variable QSAR equation was obtained via stepwise forward linear regression on an unsupervised forward selection reduced data set from an initial database. Application of the QSAR towards predicting EC2x values for all 209 PCB congeners indicated good agreement in substitution pattern trends between the experimental and estimated data sets. The QSAR model predicts a less than two-fold increase in maximal potency among all congeners outside the experimental database, and it appears that no high-potency PCB congeners with EC2x values much less than 0.2 μ M exist. Increasing RyR1-neuro toxicity equivalents with increasing homologue number and Aroclor chlorination likely reflect indirect molecular controls on toxicity, since congeners with multiple ortho substituents—the primary structural feature controlling a lack of coplanarity and resulting neurotoxicity—are more likely to be found in higher homologues.