4DPF

BACE-1 in complex with a HEA-macrocyclic type inhibitor

4DPF の概要

• エントリーDOI: 10.2210/pdb4dpf/pdb
• 関連するPDBエントリー: 4DPI
• 分子名称: Beta-secretase 1, N-[(4S,8E,11S)-4-[(1R)-1-hydroxy-2-{[3-(propan-2-yl)benzyl]amino}ethyl]-2,13-dioxo-11-phenyl-6-oxa-3,12-diazabicyclo[12.3.1]octadeca-1(18),8,14,16-tetraen-16-yl]-N-methylmethanesulfonamide (3 entities in total)
• 機能のキーワード: bace1, asp2, bace, macrocycle, 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: 44250.01

構造登録者

Lindberg, J.,Borkakoti, N.,Derbyshire, D. (登録日: 2012-02-13, 公開日: 2012-07-11, 最終更新日: 2024-10-16)

主引用文献

Sandgren, V.,Agback, T.,Johansson, P.O.,Lindberg, J.,Kvarnstrom, I.,Samuelsson, B.,Belda, O.,Dahlgren, A.
Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: design, synthesis and X-ray crystal structures of enzyme inhibitor complexes.
Bioorg.Med.Chem., 20:4377-4389, 2012

PubMed Abstract: A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed.

PubMed: 22698785
DOI: 10.1016/j.bmc.2012.05.039

実験手法

X-RAY DIFFRACTION (1.8 Å)