4ZPG: Bace1 In Complex With 8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)- 7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one

The IC50 of a beta-secretase (BACE-1) lead compound was improved approximately 200-fold from 11muM to 55nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.
PDB ID: 4ZPGDownload
MMDB ID: 131496
PDB Deposition Date: 2015/5/7
Updated in MMDB: 2015/10
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 4ZPG: monomeric; determined by author
Molecular Components in 4ZPG
Label Count Molecule
Protein (1 molecule)
Beta-secretase 1(Gene symbol: BACE1)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB