4WY6

Crystal structure of human BACE-1 bound to Compound 36

4WY6 の概要

• エントリーDOI: 10.2210/pdb4wy6/pdb
• 分子名称: Beta-secretase 1, (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine, IODIDE ION, ... (5 entities in total)
• 機能のキーワード: bace beta secretase protease, 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: 47704.37

構造登録者

Vajdos, F.F. (登録日: 2014-11-15, 公開日: 2015-03-04, 最終更新日: 2024-10-30)

主引用文献

Butler, C.R.,Brodney, M.A.,Beck, E.M.,Barreiro, G.,Nolan, C.E.,Pan, F.,Vajdos, F.,Parris, K.,Varghese, A.H.,Helal, C.J.,Lira, R.,Doran, S.D.,Riddell, D.R.,Buzon, L.M.,Dutra, J.K.,Martinez-Alsina, L.A.,Ogilvie, K.,Murray, J.C.,Young, J.M.,Atchison, K.,Robshaw, A.,Gonzales, C.,Wang, J.,Zhang, Y.,O'Neill, B.T.
Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design.
J.Med.Chem., 58:2678-2702, 2015

PubMed Abstract: The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.

PubMed: 25695670
DOI: 10.1021/jm501833t

実験手法

X-RAY DIFFRACTION (2.1 Å)