Impact/Purpose:

It has been demonstrated that chemicals introduced into the environment disrupt endocrine function. In a number of reports, experts have concluded that, "it is likely that human and domestic and wildlife species have suffered adverse health consequences from exposure to endocrine disruptor chemicals." Yet the mechanisms for these effects are only beginning to be uncovered and many of the specific chemicals and chemical classes responsible for these adverse effects may not yet have been identified. This research program has two related objectives. The first objective is to model steps in the putative mechanisms for disruption of the endocrine system by environmental chemicals using the methods of molecular modeling and from these models determine the molecular characteristics that cause a chemical to disrupt the endocrine system. The second objective is to develop (or improve existing) structure-activity relationships for specific aspects of the biological processes of endocrine disruption, employing the insight developed from the initial objective and information available in the scientific literature. A number of processes in the endocrine system have been identified as potential sites for endocrine disruption. The initial objectives of this study will be to model the specific processes of binding to the estrogen receptors, the androgen receptor, and other receptors in the endocrine system. This research will provide insight into the features of molecular structure that enable the interaction of a chemical with specific proteins in the endocrine system. These studies will provide data on the specific chemicals having activity and inform SARs for classes of chemicals similar to the ones studied and provide insight into the range of validity of other SARs.

Description:

This research will use experimentally determined structures of the estrogen receptor. The structure of estrogen and other (environmental) ligands will be used as starting points for computer docking experiments. Programs utilizing a classical molecular mechanics algorithm to quantitatively describe the interaction between atoms of different molecules will be employed. Typically, such computer programs do not account for the polarization of the interacting species. From consideration of the experimental information on binding to the estrogen receptor and the nature of the chemicals that bind to the LBD, it appears that polarization of the ligand is crucial in this binding motif. The additional interaction energy due to the polarization of the ligand will be added to the docked structure. The total energy of the docked structures will be used to determine the relative binding of various potential ligands. The energy and properties of these docked receptor-ligand complexes will additionally be computed using the "Divide-and-Conquer" semi-empirical quantum mechanical method. This method is capable of performing quantum mechanical calculations on the entire complex. The quantum mechanical calculations will provide higher quality energies to determine the capacity for binding to the receptor. In addition, properties of the ligand and the binding interaction will be computed from the wave function (also obtained from these calculations.) These properties can be used for the development of a structure-activity-relationship (SAR) or to provide insight into SARs developed in other ways.

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