Structure-based design of estrogen receptor-β selective ligands
Structure-based design of estrogen receptor-β selective ligands
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DOI：
10.1021/ja047633o
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发表时间：
2004-11-24
影响因子：
15
通讯作者：
Alvarez, JC
中科院分区：
文献类型：
--
作者：
Manas, ES;Unwalla, RJ;Alvarez, JC
我们提出了一系列基于结构的优化雌激素受体β（ER β）的选择性配体。X-射线共晶结构的这些配体复杂的ER α和ER β的描述。我们还讨论了如何使用分子建模来利用两个结合腔之间的细微差异，以优化ER β对ER的选择性（x。利用量子化学计算来深入了解选择性增强的机制。尽管在配体结合口袋中只有两个相对保守的残基取代，但当使用竞争性放射性配体结合测定法测量时，最具选择性的化合物相对于ER β对ER β具有大于100倍的选择性。
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 ER(x. 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 ERbeta when measured using a competitive radioligand binding assay.