2ZE1

X-ray structure of Bace-1 in complex with compound 6g


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.290 
  • R-Value Work: 0.248 
  • R-Value Observed: 0.250 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets.

Cole, D.C.Stock, J.R.Chopra, R.Cowling, R.Ellingboe, J.W.Fan, K.Y.Harrison, B.L.Hu, Y.Jacobsen, S.Jennings, L.D.Jin, G.Lohse, P.A.Malamas, M.S.Manas, E.S.Moore, W.J.O'Donnell, M.M.Olland, A.M.Robichaud, A.J.Svenson, K.Wu, J.Wagner, E.Bard, J.

(2008) Bioorg Med Chem Lett 18: 1063-1066

  • DOI: https://doi.org/10.1016/j.bmcl.2007.12.010
  • Primary Citation of Related Structures:  
    2ZDZ, 2ZE1

  • PubMed Abstract: 

    Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.


  • Organizational Affiliation

    Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. coledc@wyeth.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1415Homo sapiensMutation(s): 0 
Gene Names: BACE1BACE
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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
411
Query on 411

Download Ideal Coordinates CCD File 
B [auth A]3-bromo-N-[4-[1-(2-carbamimidamido-2-oxo-ethyl)-5-phenyl-pyrrol-2-yl]phenyl]benzamide
C26 H22 Br N5 O2
XWWAMKGNSKOVNS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
411 PDBBind:  2ZE1 IC50: 600 (nM) from 1 assay(s)
BindingDB:  2ZE1 IC50: min: 600, max: 5600 (nM) from 2 assay(s)
Binding MOAD:  2ZE1 IC50: 600 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.290 
  • R-Value Work: 0.248 
  • R-Value Observed: 0.250 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.026α = 90
b = 104.321β = 94.57
c = 50.465γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PROTEUM PLUSdata collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-12-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance