This program develops and maintains an interconnected system of computer programs which would allow a chemist or biologist to conveniently ask theoretical questions about molecules of interest. Using structure-activity, molecular and theoretical modeling approaches, we attempt to explain how structure determines toxicity and propose testable mechanistic hypothesis for toxic action. A theoretical model for the dioxin (Ah) receptor interaction with polychlorinated biphenyls (PCBs) and dibenzofurans based on molecular parameters and molecular mechanics has been developed and extended to interpret associated enzyme induction potencies. PCB conformational structures have been based on X-ray crystallographic measurements and energy minimization calculations. A similar stacking interaction experimental model was developed for thyroid hormone interactions with donor aromatic compounds, providing results in substantial agreement with their relative binding potencies to the triiodothyronine nuclear receptor. The important elements in this possible experimental binding model for the nuclear receptor are essentially the same as those proposed for the Ah receptor interaction with its ligands. In related work, a theoretical model for PCB (and rlated compound) interaction with human prealbumin was developed which depended on lateral chlorine substitution. Conformationally restricted PCBs were shown to be effective binding ligands for the estrogen receptor. In defining important structural properties for activity, molecular mechanics (MM2p), modified neglect of diatomic overlap (MNDO) and ab initio (STO-3G) calculations were performed on a class of similar molecules which bind the estrogen receptor. Related ab initio studies on nitroarenes established a relationship between their electron affinities and mutagenic activities.
