3IXK

Potent beta-secretase 1 inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.232 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core.

Wangsell, F.Gustafsson, K.Kvarnstrom, I.Borkakoti, N.Edlund, M.Jansson, K.Lindberg, J.Hallberg, A.Rosenquist, A.Samuelsson, B.

(2010) Eur J Med Chem 45: 870-882

  • DOI: https://doi.org/10.1016/j.ejmech.2009.11.013
  • Primary Citation of Related Structures:  
    3IXK

  • PubMed Abstract: 

    We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2'-P3' position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1'-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC(50) value of 3.1 nM.


  • Organizational Affiliation

    Department of Chemistry, Linköping University, SE-581 83 Linköping, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
405Homo sapiensMutation(s): 0 
Gene Names: BACE1BACEKIAA1149
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
929
Query on 929

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
N-[(2S,3S,5R)-1-[(3,5-difluorophenyl)methoxy]-3-hydroxy-5-methyl-6-[[(2S)-3-methyl-1-oxo-1-(phenylmethylamino)butan-2-yl]amino]-6-oxo-hexan-2-yl]-5-(methyl-methylsulfonyl-amino)-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide
C44 H53 F2 N5 O8 S
SQCCLROLILAOBD-MLLWAOEYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
929 Binding MOAD:  3IXK IC50: 6.6 (nM) from 1 assay(s)
BindingDB:  3IXK IC50: min: 6.6, max: 4500 (nM) from 2 assay(s)
PDBBind:  3IXK IC50: 6.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.282 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.232 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.838α = 90
b = 103.075β = 103.32
c = 100.499γ = 90
Software Package:
Software NamePurpose
AMoREphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description