TOWARD A MECHANISTIC UNDERSTANDING OF PCDD BIOLOGICAL-ACTIVITY BASED ON MOLECULAR ELECTROSTATIC POTENTIAL MODELING

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