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A COMPUTER DOCKING STUDY OF THE BINDING OF POLYCYCLIC AROMATIC HYDROCARBONS AND THEIR METABOLITES TO THE LIGARD-BINDING DOMAIN OF THE ESTROGEN RECEPTOR
Citation:
Brown, K. W., S. B. Little, AND J. R. Rabinowitz. A COMPUTER DOCKING STUDY OF THE BINDING OF POLYCYCLIC AROMATIC HYDROCARBONS AND THEIR METABOLITES TO THE LIGARD-BINDING DOMAIN OF THE ESTROGEN RECEPTOR. Presented at EPA Endocrine Disruptor Workshop, EPA, RTP, NC, 10/29-31/02.
Description:
Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous, anthropogenic chemicals found in the environment. In the present study, computational methods are used to evaluate their potential estrogenicity and the contribution chemicals in this class make to environmental estrogenicity. Classical docking methods, dock and affinity, are used to evaluate the potential binding affinity of chemicals in this class and their metabolitcs to the published crystal structures of the ligand-binding domain of the estrogen receptor. These methods, with a molecular mechanics interaction energy scoring function, were able to place estradiol within a root mean square deviation of 0.4 A from its binding position determined by x-ray crystallography. The scores obtained in this manner show wide variation for the PAHs and their metabolites. 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 also were 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.
(This work does not necessarily reflect EPA policy. K. W. Brown was funded by EPA/UNC Toxicology Research Program Training Agreement CT902908 and CT827206 during the performance of this study.)