4ZSM

BACE crystal structure with bicyclic aminothiazine fragment

4ZSM の概要

• エントリーDOI: 10.2210/pdb4zsm/pdb
• 関連するPDBエントリー: 4ZSP 4ZSQ 4ZSR
• 分子名称: Beta-secretase 1, (4aS,8aR)-4a,5,6,7,8,8a-hexahydro-4H-3,1-benzothiazin-2-amine, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: aspartyl, protease, beta-secretase, 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: 2
• 化学式量合計: 98372.88

構造登録者

Timm, D.E. (登録日: 2015-05-13, 公開日: 2015-06-10, 最終更新日: 2024-10-09)

主引用文献

Winneroski, L.L.,Schiffler, M.A.,Erickson, J.A.,May, P.C.,Monk, S.A.,Timm, D.E.,Audia, J.E.,Beck, J.P.,Boggs, L.N.,Borders, A.R.,Boyer, R.D.,Brier, R.A.,Hudziak, K.J.,Klimkowski, V.J.,Garcia Losada, P.,Mathes, B.M.,Stout, S.L.,Watson, B.M.,Mergott, D.J.
Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.
Bioorg.Med.Chem., 23:3260-3268, 2015

PubMed Abstract: The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described.

PubMed: 26001341
DOI: 10.1016/j.bmc.2015.04.062

実験手法

X-RAY DIFFRACTION (1.96 Å)