Development of a Computational Assay for the Estrogen Receptor
Final rept. 1 Jul 2005-30 Jun 2006
HAMILTON COLL CLINTON NY
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Estrogen Receptor alpha alpha ER, binds estradiol, initiating a cascade of events that leads to alpha ER-positive breast cancer. The alpha ER binds the FDA approved drug for breast cancer, tamoxifen, and also raloxifene, with high affinity. The crystal structures of the alpha ER-estradiol, alpha ER- tamoxifen, and ER-raloxifene complexes reveal that estradiol binding changes the conformation of helix 12 H12 so that co-regulatory proteins can bind and activate transcription, whereas tamoxifen and raloxifene binding displaces H12 to a different position that prevents the binding of co-regulatory proteins. We have successfully combined MD QM methods in an innovative way to develop a computational assay that will allow for the development of novel lead compounds that should be active against breast cancer. Our test system consists of estradiol, tamoxifen, and several known raloxifene analogs. MD simulations were performed for 3-5 nanoseconds on a truncated alpha ER protein bound to different ligands. These simulations generated input structures for a variety of methods, ranging from MM to QM, for determining energy the binding energy of ligands to the alpha ER. We have determined the optimal method for correlating binding energies to experimental relative binding affinitites RBAs. We will use this assay to design novel inhibitors with high-predicted activity.
- Medicine and Medical Research