A HYPOTHESIS ON THE MECHANISM OF PCDD BIOLOGICAL-ACTIVITY BASED ON MOLECULAR ELECTROSTATIC POTENTIAL MODELING .2.

We have focused our attention on the electrostatic properties of a set of PCDDs, polychlorinated dibenzo-p-dioxins, of known binding affinit ies for the Ah receptor. In this paper we analyze the molecular electr ostatic 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 ei ght PCDDs. A visual analysis of the MEP distributions shows that the s tepwise differentiation from the electrostatic characteristics typical of the most active isomers is associated with a decrease in binding a ffinity; 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 affini ties for the whole set of isomers. The information retained in the ove rall MEP distributions is summed up in a few carefully chosen descript ors, i.e. the MEP values in particular points located around the molec ules. A statistical analysis performed by linear and non-linear method s elucidates the electrostatic requirements effective in the recogniti on process with the Ah receptor; from this there also emerges a physic al interpretation of the process. In particular, two different types o f electrostatic feature associated with two subsets of PCDD isomers ap pear to be recognized by the Ah receptor.