Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors
Abstract
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
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2005
- Accession Number
- ADA446323
Entities
People
- Brian J. Bennion
- Felice Lightstone
- Kris Kulp
- Monique Cosman
Organizations
- University of California