3U6A

Rational Design and Synthesis of Aminopiperazinones as Beta Secretase (BACE) Inhibitors

3U6A の概要

• エントリーDOI: 10.2210/pdb3u6a/pdb
• 分子名称: Beta-secretase 1, N-{3-[(2R)-6-amino-2,4-dimethyl-3-oxo-2,3,4,5-tetrahydropyrazin-2-yl]phenyl}-5-chloropyridine-2-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: beta-site app cleaving enzyme 1, 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: 3
• 化学式量合計: 132131.68

構造登録者

Spurlino, J.C.,Alexander, R.S. (登録日: 2011-10-12, 公開日: 2011-11-09, 最終更新日: 2024-11-06)

主引用文献

Tresadern, G.,Delgado, F.,Delgado, O.,Gijsen, H.,Macdonald, G.J.,Moechars, D.,Rombouts, F.,Alexander, R.,Spurlino, J.,Van Gool, M.,Vega, J.A.,Trabanco, A.A.
Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors.
Bioorg.Med.Chem.Lett., 21:7255-7260, 2011

PubMed Abstract: Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

PubMed: 22071305
DOI: 10.1016/j.bmcl.2011.10.050

実験手法

X-RAY DIFFRACTION (2.199 Å)