3UDY

Crystal Structure of BACE with Compound 11

3UDY の概要

• エントリーDOI: 10.2210/pdb3udy/pdb
• 関連するPDBエントリー: 3UDH 3UDJ 3UDK 3UDM 3UDN 3UDP 3UDQ 3UDR
• 分子名称: Beta-secretase 1, 3-bromo-4-cyanobenzyl (3S,5'R)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: 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: 46002.79

構造登録者

Efremov, I.V.,Vajdos, F.F.,Borzilleri, K.,Capetta, S.,Dorff, P.,Dutra, J.,Mansour, M.,Oborski, C.,O'Connell, T.,O'Sullivan, T.J.,Pandit, J.,Wang, H.,Withka, J. (登録日: 2011-10-28, 公開日: 2012-04-18, 最終更新日: 2024-11-20)

主引用文献

Efremov, I.V.,Vajdos, F.F.,Borzilleri, K.A.,Capetta, S.,Chen, H.,Dorff, P.H.,Dutra, J.K.,Goldstein, S.W.,Mansour, M.,McColl, A.,Noell, S.,Oborski, C.E.,O'Connell, T.N.,O'Sullivan, T.J.,Pandit, J.,Wang, H.,Wei, B.,Withka, J.M.
Discovery and optimization of a novel spiropyrrolidine inhibitor of {beta}-secretase (BACE1) through fragment-based drug design.
J.Med.Chem., 55:9069-9088, 2012

PubMed Abstract: The aspartyl protease β-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aβ-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.

PubMed: 22468999
DOI: 10.1021/jm201715d

実験手法

X-RAY DIFFRACTION (2 Å)