A new structure-activity model for Ah receptor binding. Polychlorinated dibenzo-p-dioxins and dibenzofurans

A new structure-affinity model for the aromatic hydrocarbon (Ah) receptor is reported. The proposed mathematical model completely eliminates multiple regression analysis in its formulation and overcomes the cross-class comparison inherent to classical quantitative structure-activity relationships. Taking the polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) as model xenobiotics, the binding affinity of a PCDD relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is shown to be analytically related to the electron affinities, entropies, and lipophilicities of PCDD and TCDD. From the calculated dissociation constants of PCDD-Ah receptor complexes, the corresponding equilibrium constants of PCDF-Ah complexes could be computed, in agreement with the experimental observation that the trend in the binding affinities of PCDDs and PCDFs to the Ah receptor are similar. The reported model is capable of quantitatively explaining the quantitatively estimating the in vitro binding affinities of PCDDs, PCDFs, and related xenobiotics to the Ah receptor. Therefore, a halogenated aromatic compound is expected to have a higher affinity for the cytosolic protein than TCDD if it is less lipophilic and has a higher electron affinity and lower entropy. Furthermore, the affinities of structurally related polychlorinated aromatic xenobiotics for the Ah receptor could be computed from their entropies and electron affinities.