Prediction of endocrine disruptors based on a new structure-activity relationship for sex and environmental hormones using chemical hardness concept

Abstract

Classification of the relationship between electronic structures and biological activities of endocrine disruptors (so-called environmental hormones) was attempted using the parameters of absolute hardness (η), absolute electronegativity (χ), and global softness (S), approximately defined as η=1/2(εLUMO-εHOMO), χ=-1/2(εHOMO+εLUMO), and S=1/η, respectively, based on the hardness concept. The strength of binding affinity and toxicity of the chemicals were approximately proportional to the absolute hardness, and laterally toxic chlorinated PCDDs, PCBs, and DDTs are classified as chemically soft. Here we found that the electronic structures of environmental hormones can be classified into four main groups: 17β-estradiol type (group I), testosterone type (group II), thyroxine type (group III), and HCH (hexachlorocyclohexane) type (group IV). Therefore, if we can predict the coordinate (χ, η) of the electronic structure of one chemical on the η-χ activity diagram, we would be able to predict the receptor with which the chemicals (environmental hormones) interact. For instance, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is classified in group III, therefore, it would bind with the thyroid receptor more than the estrogen receptor (group I). It appears that dibutyl phthalate would not interact with estrogen receptor because it does not belong to group I. In addition, the coordinates of these four groups do not complementarily overlap with the electronic structures of 20 natural amino acid residues. The η-χ activity diagram is a new tool for the prediction of the toxicity and biological activity of environmental hormones.