Dioxin-Type Activity for Polyhalogenated Arylic Derivatives. A QSAR Model Based on MTD-Method

Abstract

QSARs by the Minimal Steric/Topologic Difference (MTD)-method were performed for general toxicity, hepatic cytosol receptor binding and aryl hydrocarbon hydroxylase induction on polychlorinated and polybrominated derivatives of dibenzo-p-dioxin, dibenzofuran and biphenyl. Low energy conformations selected by molecular mechanics calculations and superpositions of the considered structures for the construction of the hypermolecule were performed using the COSMIC molecular modelling package. The multiconformational-MTD-method was used. Correlation coefficients of r = 0.8 to 0.9 were obtained as well as good cross-validation results, for series of up to 70 compounds. Conformational analysis of flexible molecules suggests their accommodation in the receptor site also in non planar conformations corresponding to the first stable one (minimum energy costs) above the global minimum. A common optimised receptor site can be attributed for all series of compounds, with a rather high symmetry, which suggests that these compounds produce gene activation by dimerization of their receptor protein. The high toxicity of dioxin-type compounds could be explained by their high stability that produce long lasting, abnormally high levels of some detoxification enzymes—without toxic effects at their low and normal levels.