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MODELING THE BINDING OF THE METABOLITES OF SOME POLYCYCLIC AROMTIC HYDROCARBONS TO THE LIGAND BINDING DOMAIN OF THE ESTROGEN RECEPTOR
Citation:
Rabinowitz, J. R., S. B. Little, AND K. W. Brown. MODELING THE BINDING OF THE METABOLITES OF SOME POLYCYCLIC AROMTIC HYDROCARBONS TO THE LIGAND BINDING DOMAIN OF THE ESTROGEN RECEPTOR. Presented at American Assoc. of Cancer Research Meeting, Washington, DC, 07/11-14/03.
Description:
Modeling the binding of the metabolites of some Polycyclic Aromatic Hydrocarbons to the ligand binding domain of the estrogen receptor
James Rabinowitz, Stephen Little, Katrina Brown, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC; University of Pittsburgh at Greensburg, Greensburg, PA.
There are many reports of environmental estrogenicity in the literature. Yet it has been difficult to identify the specific chemicals responsible for these effects. Polycyclic Aromatic Hydrocarbons (PAHs) are a class of ubiquitous, anthropogenic chemicals found in the environment. Some class members have been shown to be animal carcinogens in a variety of systems, including estrogen dependent tissue. In the present study, we use computational methods to evaluate their potential estrogenicity and the possible contribution chemicals in this class could make to environmental estrogenicity. Classical docking methods are used to evaluate the potential binding affinity of specific PAH metabolites to the published crystal structures of the Ligand Binding Domain of the Estrogen Receptor. These methods were able to place estradiol within an RMSD of 0.4 Angstrom from its binding position as determined by x-ray crystallography. These methods show wide variation in the strength and mode of binding of the PAH metabolites studied. They depend on PAH type and the three dimensional structure of the metabolites. For example(-)-anti-benzo[c]phenanthrene diolepoxide is a much better binder in this model than the (+) enantiomer. A few dominant modes of binding have been identified and will be presented. These results will be compared to the results for known binders. Semi-empirical quantum mechanical methods were also used to compute the interaction energy of the most stable structures obtained from the classical computer docking experiments. These quantum mechanical calculations provide a quantitative description of the interaction between the ligand and the receptor and contain elements that are omitted from the classical scoring function. The comparison of these results demonstrates the importance of the nonclassical interaction terms for molecules that have pi electron systems. The contribution of the interaction between amino acids critical to binding and these potential ligands has also been computed using quantum mechanical methods. This study of PAH metabolites, serves as a model for considering the capacity of other environmental chemical to interact with the estrogen receptor. This work does not necessarily reflect EPA policy. K. W. Brown was funded by EPA/UNC Toxicology Research Program Training Agreement CT902908 and CT8272