Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of ß-Secretase.
J Med Chem
; 59(8): 3732-49, 2016 04 28.
Article
in En
| MEDLINE
| ID: mdl-26978477
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, ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Magnetic Resonance Spectroscopy
/
Enzyme Inhibitors
/
Amyloid Precursor Protein Secretases
Type of study:
Prognostic_studies
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2016
Document type:
Article
Affiliation country:
Estados Unidos