Models of Polychlorinated Dibenzodioxins, Dibenzofurans, and Biphenyls Binding Affinity to the Aryl Hydrocarbon Receptor Developed Using ¹³C NMR Data

Quantitative spectroscopic data-activity relationship (QSDAR) models for polychlorinated dibenzofurans (PCDFs), dibenzodioxins (PCDDs), and biphenyls (PCBs) binding to the aryl hydrocarbon receptor (AhR) have been developed based on simulated ¹³C nuclear magnetic resonance (NMR) data. All the models were based on multiple linear regression of comparative spectral analysis (CoSA) between compounds. A 1.0 ppm resolution CoSA model for 26 PCDF compounds based on chemical shifts in five bins had an explained variance (r²) of 0.93 and a leave-one-out (LOO) cross-validated variance (q²) of 0.90. A 2.0 ppm resolution CoSA model for 14 PCDD compounds based on chemical shifts in five bins had an r² of 0.91 and a q² of 0.81. The 1.0 ppm resolution CoSA model for 12 PCB compounds based on chemical shifts in five bins had an r² of 0.87 and a q² of 0.45. The models with more compounds had a better q² because there are more multiple chemical shift populated bins available on which to base the linear regression. A 1.0 ppm resolution CoSA model for all 52 compounds that was based on chemical shifts in 12 bins had an r² of 0.85 and q² of 0.71. A canonical variance analysis of the 1.0 ppm CoSA model for all 52 compounds when they were separated into 27 strong binding and 25 weak binding compounds was 98% correct. Conventional quantitative structure-activity relationship (QSAR) modeling suffer from errors introduced by the assumptions and approximations involved in calculated electrostatic potentials and the molecular alignment process. QSDAR modeling is not limited by such errors since electrostatic potential calculations and molecular alignment are not done. The QSDAR models provide a rapid, simple and valid way to model the PCDF, PCDD, and PCB binding activity in relation to the aryl hydrocarbon receptor (AhR).