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. Our experience using the limited form in which our system now exists has amply proven the value of a unified approach, but the fast pace of hardware and software developments in this field, together with the complexity of the individual components has so far precluded the existence of a """"""""ready made"""""""" solution to our needs. In association with an experimental group the program continues to investigate the molecular interaction of the halogenated aromatic hydrocarbons, an important class of toxic environmental agents. Early studies focusing on polychlorinated biphenyl (PCBs) and related compounds led to the development of a theoretical model for the dioxin or Ah receptor based on molecular parameters and molecular mechanics. Related studies with the chlorinated dioxins identified common molecular properties with the thyroid hormones which enable them to present a planar face and lateral halogens in interactions with proteins. Experimental studies are investigating the binding behavior of PCBs with specific thyroxine binding proteins along with molecular dynamic simulation of these binding events. In other work we are examining the use of energy minimization programs to accurately predict the energies and shapes of metastable conformers of drugs and toxic chemicals. A theoretical study of the minimum energy structures of diethylstilbestrol and its analogs by molecular mechanics (MM2P), MNDO and ab initio calculations found that MM2P agrees most closely with X-ray for all cases studied.
