Download MendeleyStructure-Based Design of Estrogen Receptor-Beta Selective Ligands
Manas, E.S., Unwalla, R.J., Xu, Z.B., Malamas, M.S., Miller, C.P., Harris, H.A., Hsiao, C., Akopian, T., Hum, W.T., Malakian, K., Wolfrom, S., Bapat, A., Bhat, R.A., Stahl, M.L., Somers, W.S., Alvarez, J.C.(2004) J Am Chem Soc 126: 15106-15119
- PubMed: 15548008
- DOI: https://doi.org/10.1021/ja047633o
- Primary Citation of Related Structures:
1U9E, 1X76, 1X78, 1X7B, 1X7E - PubMed Abstract:
We present the structure-based optimization of a series of estrogen receptor-beta (ERbeta) selective ligands. X-ray cocrystal structures of these ligands complexed to both ERalpha and ERbeta are described. We also discuss how molecular modeling was used to take advantage of subtle differences between the two binding cavities in order to optimize selectivity for ERbeta over ERalpha. Quantum chemical calculations are utilized to gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservative residue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERbeta relative to ERalpha when measured using a competitive radioligand binding assay.
Organizational Affiliation:
Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. [email protected]
