Toward a mechanistic understanding of PCDD biological activity based on molecular electrostatic potential modeling

The mechanism of action of polychlorinated dibenzo-p-dioxins (PCDDs) and related compounds has received extensive study but has not yet been completely elucidated. Most of the toxic responses and biological effects appear to be mediated by the binding to the Ah receptor. Our study is focused on the ligand-receptor complex which has a key role in the dioxin mechanism of action. In this paper we seek patterns in the molecular electrostatic potential (MEP) of PCDDs that can be related to their binding affinity. To this aim we analyse the three dimensional distributions of the MEP, obtained in the framework of the HF-SCF theory by ab initio calculations with the 3-21G basis set. A series of isomers showing a significant range of binding affinity values are studied: the choice of isomers belonging to the tetrachlorinated dibenzo-p-dioxin (TCDD) congener group allows us to study the effects of substitution patterns; the comparison with other PCDDs leads us to study the effects of different degrees of chlorination. On the basis of the significant electrostatic features we propose a structural hypothesis for the activity. Relevant information retained in the overall MEP distribution is summarized in a few descriptors, i.e. the MEP values in points properly located around the molecules. A good quantitative model is obtained which relates these descriptors with the experimental pEC50 values