2OHL: X-ray Crystal Structure of Beta Secretase Complexed With 2- Aminoquinoline

Citation:
Abstract
This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment.
PDB ID: 2OHLDownload
MMDB ID: 45205
PDB Deposition Date: 2007/1/10
Updated in MMDB: 2012/11 
Experimental Method:
x-ray diffraction
Resolution: 2.65  Å
Source Organism:
Similar Structures:
Biological Unit for 2OHL: monomeric; determined by author
Molecular Components in 2OHL
Label Count Molecule
Protein (1 molecule)
1
Beta-secretase 1
(Gene: BACE1)
Molecule annotation
Chemicals (5 molecules)
1
3
2
1
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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