3UDM: Crystal Structure of BACE with Compound 8

Citation:
Abstract
The aspartyl protease beta-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Abeta-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.
PDB ID: 3UDMDownload
MMDB ID: 98822
PDB Deposition Date: 2011/10/28
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.94  Å
Source Organism:
Similar Structures:
Biological Unit for 3UDM: monomeric; determined by author
Molecular Components in 3UDM
Label Count Molecule
Protein (1 molecule)
1
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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