4ACU

Aminoimidazoles as BACE-1 Inhibitors. X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 14


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy.

Swahn, B.M.Holenz, J.Kihlstrom, J.Kolmodin, K.Lindstrom, J.Plobeck, N.Rotticci, D.Sehgelmeble, F.Sundstrom, M.Berg, S.v.Falting, J.Georgievska, B.Gustavsson, S.Neelissen, J.Ek, M.Olsson, L.L.Berg, S.

(2012) Bioorg Med Chem Lett 22: 1854-1859

  • DOI: https://doi.org/10.1016/j.bmcl.2012.01.079
  • Primary Citation of Related Structures:  
    4ACU, 4ACX

  • PubMed Abstract: 

    The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300μmol/kg (R)-25 and efflux inhibitor GF120918 the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76%.


  • Organizational Affiliation

    Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-15185 Södertälje, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-SECRETASE 1411Homo sapiensMutation(s): 2 
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
QN7 Binding MOAD:  4ACU IC50: 40.7 (nM) from 1 assay(s)
BindingDB:  4ACU IC50: min: 20, max: 31 (nM) from 2 assay(s)
PDBBind:  4ACU IC50: 40.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.588α = 90
b = 76.372β = 90
c = 104.213γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-29
    Type: Initial release
  • Version 1.1: 2018-02-14
    Changes: Database references, Structure summary