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MODELING THE EFFECTS OF FLEXIBILITY ON THE BINDING OF ENVIRONMENTAL ESTROGENS TO THE ESTROGEN RECEPTOR
Little, S. B., J. R. Rabinowitz, AND K. W. Brown. MODELING THE EFFECTS OF FLEXIBILITY ON THE BINDING OF ENVIRONMENTAL ESTROGENS TO THE ESTROGEN RECEPTOR. Presented at Gordon Conference on Computer Aided Drug Design, Tilton,NH, Tilton, NH, July 20-25, 2003.
Modeling the effects of flexibility on the binding of environmental estrogens to the estrogen receptor
There are many reports of environmental endocrine disruption in the literature, yet it has been difficult to identify the specific chemicals responsible for these effects. For many of the chemicals found in the environment there is no information on their potential as endocrine disruptors. Polycylic Aromatic Hydrocarbons (PAHs) and their metabolites represent a class of chemicals for which there is incomplete evidence of estrogenicity of individual chemicals. In order to understand the potential of chemicals in this class of ubiquitous environmental contaminants to disrupt endocrine function by binding to the estrogen receptor, we have performed computer molecular docking experiments.
The estrogen receptor is a promiscuous receptor and has been shown to have a flexible binding pocket. There is crystallographic data for the structure of this receptor bound to different ligands. In order to study the importance of flexibility on (weak) binding, we have docked potential environmental ligands into multiple models developed from the crystal structures of the receptor. Classical docking calculations with flexible ligands and the rigid receptor conformations have been performed and additional docking studies have been performed with Monte Carlo/ Simulated Annealing methods. Both the ordering and absolute binding energy scores for a series of PAH metabolites depends on the particular crystal structure used to develop the docking model. Quantum mechanical calculations have also been performed for comparison.
This abstract does not necessarily reflect EPA policy.