Discovery and X-ray Crystallographic Analysis of a Spiropiperidine Iminohydantoin Inhibitor of β-Secretase
Discovery and X-ray Crystallographic Analysis of a Spiropiperidine Iminohydantoin Inhibitor of β-Secretase
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DOI：
10.1021/jm800914n
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发表时间：
2008-10-23
影响因子：
7.3
通讯作者：
Vacca, Joseph P.
中科院分区：
文献类型：
--
作者：
Barrow, James C.;Stauffer, Shaun R.;Vacca, Joseph P.
BACE-1 酶抑制剂浓度为 100.μM 的高通量筛选揭示了一种新型螺哌啶亚氨基乙内酰脲天冬氨酰蛋白酶抑制剂模板。与 BACE-1 的 X 射线共晶结构揭示了一种新的结合模式，抑制剂通过桥接水分子与催化天冬氨酸相互作用。以晶体结构为指导，设计了具有良好脑渗透性的有效化合物。
A high-throughput screen at 100.mu M inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.