A hypothesis on the mechanism of PCDD biological activity based on molecular electrostatic potential modeling. Part 2

Abstract

We have focused our attention on the electrostatic properties of a set of PCDDs, polychlorinated dibenzo- p-dioxins, of known binding affinities for the Ah receptor. In this paper we analyze the molecular electrostatic potential (MEP) of the six selected isomers, 2,3,6-TrCDD, 1,2,4,7,8-PeCDD, 1,2,3,4-TCDD, 1,2,3,4,7-PeCDD, 1,2,4-TrCDD and 1-MCDD, in order to validate the results previously obtained on a test set of eight PCDDs. A visual analysis of the MEP distributions shows that the stepwise differentiation from the electrostatic characteristics typical of the most active isomers is associated with a decrease in binding affinity; however, the simultaneous occurrence of different trends for different electrostatic requirements for activity does not make for a simple definition of the relationships between MEP patterns and affinities for the whole set of isomers. The information retained in the overall MEP distributions is summed up in a few carefully chosen descriptors, i.e. the MEP values in particular points located around the molecules. A statistical analysis performed by linear and non-linear methods elucidates the electrostatic requirements effective in the recognition process with the Ah receptor; from this there also emerges a physical interpretation of the process. In particular, two different types of electrostatic feature associated with two subsets of PCDD isomers appear to be recognized by the Ah receptor.