5I3V

Crystal structure of BACE1 in complex with aminoquinoline compound 1

5I3V の概要

• エントリーDOI: 10.2210/pdb5i3v/pdb
• 関連するPDBエントリー: 5I3W 5I3X 5I3Y
• 分子名称: Beta-secretase 1, IODIDE ION, (2R)-3-[2-amino-6-(3-methylpyridin-2-yl)quinolin-3-yl]-N-(3,3-dimethylbutyl)-2-methylpropanamide, ... (5 entities in total)
• 機能のキーワード: aspartic protease, amyloid precursor protein, alzheimer's disease, 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: 46699.80

構造登録者

Whittington, D.A.,Long, A.M. (登録日: 2016-02-11, 公開日: 2016-03-30, 最終更新日: 2024-11-06)

主引用文献

Jordan, J.B.,Whittington, D.A.,Bartberger, M.D.,Sickmier, E.A.,Chen, K.,Cheng, Y.,Judd, T.
Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of beta-Secretase.
J.Med.Chem., 59:3732-3749, 2016

PubMed Abstract: Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with (19)F NMR-based methods has been shown to provide several advantages over (1)H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of (19)F-based fragment screening by detailing the identification of a second-site fragment through (19)F NMR screening that binds to a specific pocket of the aspartic acid protease, β-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment-linking approach, which ultimately yielded a molecule exhibiting a more than 360-fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling.

PubMed: 26978477
DOI: 10.1021/acs.jmedchem.5b01917

実験手法

X-RAY DIFFRACTION (1.62 Å)