ERβ ligands.: 3.: Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERβ selectivity
ERβ ligands.: 3.: Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERβ selectivity
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DOI：
10.1021/jm058173s
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发表时间：
2005-06-16
影响因子：
7.3
通讯作者：
Harris, HA
中科院分区：
文献类型：
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作者：
Mewshaw, RE;Edsall, RJ;Harris, HA
为了鉴定内质网选择性配体，我们探索了2-苯基萘支架作为染料木素的简化版本。在对接研究的帮助下，2-苯基萘模板的1、4和8位被预测为使用两种不同的结合方向提高ER选择性的最有潜力的位置。这两个取向都有模拟染料木素A环的苯酚部分。当与ERβ结合时，有几个化合物被预测采用与染料木素相似的取向，观察到比染料木素具有更高的ER亲和力和选择性。我们利用的第二个方向，不同于Genistein与ERβ结合时的方向，导致发现了几个比Genistein具有更好的ER选择性和亲和力的化合物。两个ER选择性化合物(即15和47)的X-射线结构证实了交替结合模式，并表明1和8位取代基是诱导选择性的原因。一种化合物(即47，Way-202196)被进一步研究并发现在两种炎症模型中有效，这表明靶向ER可能在治疗某些慢性炎症性疾病方面有用。
The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ER beta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ER beta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.