3IND

Bace1 with the aminohydantoin Compound 29

3IND の概要

• エントリーDOI: 10.2210/pdb3ind/pdb
• 関連するPDBエントリー: 3INE 3INF 3INH
• 分子名称: Beta-secretase 1, (5S)-2-amino-3-methyl-5-phenyl-5-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]-3,5-dihydro-4H-imidazol-4-one (3 entities in total)
• 機能のキーワード: bace1, xray, inhibitor, alternative splicing, aspartyl protease, disulfide bond, glycoprotein, hydrolase, membrane, polymorphism, protease, transmembrane, zymogen
• 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: 46764.41

構造登録者

Olland, A.M.,Chopra, R. (登録日: 2009-08-12, 公開日: 2010-03-02, 最終更新日: 2024-11-06)

主引用文献

Malamas, M.S.,Erdei, J.,Gunawan, I.,Turner, J.,Hu, Y.,Wagner, E.,Fan, K.,Chopra, R.,Olland, A.,Bard, J.,Jacobsen, S.,Magolda, R.L.,Pangalos, M.,Robichaud, A.J.
Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors.
J.Med.Chem., 53:1146-1158, 2010

PubMed Abstract: The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).

PubMed: 19968289
DOI: 10.1021/jm901414e

実験手法

X-RAY DIFFRACTION (2.246 Å)