ChemInform Abstract: MOLECULAR INTERACTIONS OF TOXIC CHLORINATED DIBENZO‐P‐DIOXINS AND DIBENZOFURANS WITH THYROXINE BINDING PREALBUMIN

Abstract

The interactions of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds with prealbumin, a model for the nuclear thyroid hormone receptor, have been studied with use of computer graphics and predictions made regarding relative binding affinities for such structures. These modeling predictions were tested by experimentally measuring the binding affinities of dioxin and furan analogues. The results were in general agreement with the modeling predictions and demonstrated that such compounds could be effective competitive binding ligands for thyroxine-specific binding sites in prealbumin. The computer modeling work also demonstrates the importance of lateral chlorine substitution in the binding of these toxic compounds. The prealbumin interaction model should be of use in investigating the structure-toxicity relationships of these classes of toxic compounds. Thus, if prealbumin is a model for the nuclear thyroid hormone receptor, this work would also have major implications bearing on the mechanism of dioxin toxicity and the potential of these compounds to function as potent and persistent thyroxine agonists. A new cooperative receptor mechanism for dioxin toxic action is proposed.