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Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors

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Final rept. 2 Aug 2003-1 Aug 2005

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In an effort to treat breast cancer, selective estrogen receptor modulators SERMs have been used to modulate the estrogen-signaling pathway with mixed results 1. A classic example of a SERM is tamoxifen. When used as a therapeutic for a limited time, tamoxifen is effective in disrupting the estrogen-signaling pathway. Unfortunately, with prolonged use, breast tumor cells become resistant to tamoxifen and are able to use the bioactivated metabolite of tamoxifen to interact with co-activators that activate the estrogen-signaling pathway, reversing its original role 1. An alternative therapeutic approach is to target the binding site of the co-activator protein. Recent studies have shown that some small molecules may bind in sites e.g. co-activator site other than the estradiol binding site 2 and still disrupt the estrogen-signaling pathway. By binding in the co-activator site while estradiol is bound in the estrogen receptor ER ligand binding domain LBD, these small molecules act as co-activator binding inhibitors CBIs because the co-activator proteins can no longer bind thus, gene transcription is inhibited. Potentially, these CBIs can act as a new therapeutics against environmental or natural agonists of ERalpha. Quantitative structure-activity relationship QSAR studies have been used to develop therapeutics that will compete and bind in the estradiol binding site of the ERalpha LBD 3-5. Because these studies have focused on the estradiol binding site, new potential ER disruptors that bind in the co-activator site have been missed. Our proposal focuses on developing a new computational approach to predict therapeutically useful ERalpha disruptors by investigating CBIs binding to the co-activator site in conjunction with estrogenic compounds bound in the estradiol site

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  • Biochemistry
  • Medicine and Medical Research

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