Structure-Based Design of Estrogen Receptor- Selective Ligands
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- 作者：Eric S. Manas ; Rayomand J. Unwalla ; Zhang B. Xu ; Michael S. Malamas ; Chris P. Miller ; Heather A. Harris ; Chulai Hsiao ; Tatos Akopian ; Wah-Tung Hum ; Karl Malakian ; Scott Wolfrom ; Ashok Bapat ; Ramesh A.
- 刊名：Journal of the American Chemical Society
- 出版年：2004
- 出版时间：November 24, 2004
- 年：2004
- 卷：126
- 期：46
- 页码：15106 - 15119
- 全文大小：1213K
- 年卷期：v.126,no.46(November 24, 2004)
- ISSN：1520-5126
文摘
We present the structure-based optimization of a series of estrogen receptor-
ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> (ERges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">) selectiveligands. X-ray cocrystal structures of these ligands complexed to both ERges/gifchars/alpha.gif" BORDER=0> and ERges/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> are described. Wealso discuss how molecular modeling was used to take advantage of subtle differences between the twobinding cavities in order to optimize selectivity for ERges/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> over ERges/gifchars/alpha.gif" BORDER=0>. Quantum chemical calculations are utilizedto gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservativeresidue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERges/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> relative to ERges/gifchars/alpha.gif" BORDER=0> when measured using a competitive radioligand binding assay.