4IVS

Crystal structure of BACE1 with its inhibitor

4IVS の概要

• エントリーDOI: 10.2210/pdb4ivs/pdb
• 関連するPDBエントリー: 4IVT
• 分子名称: Beta-secretase 1, N-{N-[4-(acetylamino)-3,5-dichlorobenzyl]carbamimidoyl}-2-(6-cyano-1H-indol-1-yl)acetamide (3 entities in total)
• 機能のキーワード: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 48680.24

構造登録者

Chen, T.T.,Li, L.,Chen, W.Y.,Xu, Y.C. (登録日: 2013-01-23, 公開日: 2013-11-13, 最終更新日: 2024-10-16)

主引用文献

Zou, Y.,Li, L.,Chen, W.Y.,Chen, T.T.,Ma, L.,Wang, X.,Xiong, B.,Xu, Y.C.,Shen, J.
Virtual screening and structure-based discovery of indole acylguanidines as potent beta-secretase (BACE1) inhibitors
Molecules, 18:5706-5722, 2013

PubMed Abstract: Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.

PubMed: 23681056
DOI: 10.3390/molecules18055706

実験手法

X-RAY DIFFRACTION (2.636 Å)