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5I3Y

Crystal structure of BACE1 in complex with aminoquinoline inhibitor 9

Summary for 5I3Y
Entry DOI10.2210/pdb5i3y/pdb
Related5I3V 5I3W 5I3X
DescriptorBeta-secretase 1, N-(6-{2-[2-(2-amino-3-{3-[(3,3-dimethylbutyl)amino]-3-oxopropyl}quinolin-6-yl)phenyl]ethyl}pyridin-3-yl)-4-fluorobenzamide (3 entities in total)
Functional Keywordsaspartic protease, amyloid precursor protein, alzheimer's disease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHomo sapiens (Human)
Cellular locationMembrane; Single-pass type I membrane protein: P56817
Total number of polymer chains1
Total formula weight46440.20
Authors
Whittington, D.A.,Long, A.M. (deposition date: 2016-02-11, release date: 2016-03-30, Last modification date: 2023-09-27)
Primary citationJordan, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.15 Å)
Structure validation

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