Structure-based design and synthesis of novel P2/P3 modified, non-peptidic β-secretase (BACE-1) inhibitors
Structure-based design and synthesis of novel P2/P3 modified, non-peptidic β-secretase (BACE-1) inhibitors
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DOI：
10.1016/j.bmcl.2010.01.139
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发表时间：
2010-03-15
影响因子：
2.7
通讯作者：
Tintelnot-Blomley, Marina
中科院分区：
文献类型：
--
作者：
Hanessian, Stephen;Shao, Zhihui;Tintelnot-Blomley, Marina
从肽模拟物BACE-1抑制剂开始，包括P2/P3肽键的P2氨基酸被刚性3-氨甲基环己烷羧酸取代。共结晶揭示了一种意想不到的结合模式，其中P3/P4酰胺键被置于S3口袋中，导致新的氢键相互作用模式。基于该结构的进一步优化产生了对BACE-2和组织蛋白酶D具有选择性的高效BACE-1抑制剂。(C)2010爱思唯尔有限公司版权所有。
Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D. (C) 2010 Elsevier Ltd. All rights reserved.