5I3W: Crystal structure of BACE1 in complex with 2-aminooxazoline-3-azaxanthene inhibitor 2

Citation:
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, beta-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.
PDB ID: 5I3WDownload
MMDB ID: 137986
PDB Deposition Date: 2016/2/11
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.15  Å
Source Organism:
Similar Structures:
Biological Unit for 5I3W: monomeric; determined by author and by software (PISA)
Molecular Components in 5I3W
Label Count Molecule
Protein (1 molecule)
1
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemicals (6 molecules)
1
3
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.