2WF1

Human BACE-1 in complex with 7-ethyl-N-((1S,2R)-2-hydroxy-3-(((3-(methyloxy)phenyl(methyl)amino)-1-(phenylmethyl)propyl)-1-methyl-3,4- dihydro-1H-(1,2,5)thiadiazepino(3,4,5-hi)indole-9-carboxamide 2,2- dioxide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.184 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Second Generation of Bace-1 Inhibitors Part 2: Optimisation of the Non-Prime Side Substituent.

Charrier, N.Clarke, B.Demont, E.Dingwall, C.Dunsdon, R.Hawkins, J.Hubbard, J.Hussain, I.Maile, G.Matico, R.Mosley, J.Naylor, A.O'Brien, A.Redshaw, S.Rowland, P.Soleil, V.Smith, K.J.Sweitzer, S.Theobald, P.Vesey, D.Walter, D.S.Wayne, G.

(2009) Bioorg Med Chem Lett 19: 3669

  • DOI: https://doi.org/10.1016/j.bmcl.2009.03.150
  • Primary Citation of Related Structures:  
    2WF1, 2WF2, 2WF3

  • PubMed Abstract: 

    Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.


  • Organizational Affiliation

    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-SECRETASE 1392Homo sapiensMutation(s): 4 
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
ZY1
Query on ZY1

Download Ideal Coordinates CCD File 
B [auth A]N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-7-ethyl-1-methyl-3,4-dihydro-1H-[1,2,5]thiadiazepino[3,4,5-hi]indole-9-carboxamide 2,2-dioxide
C32 H38 N4 O5 S
MNGUVHPNHVMEDL-MFMCTBQISA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ZY1 PDBBind:  2WF1 IC50: 2 (nM) from 1 assay(s)
BindingDB:  2WF1 IC50: 2 (nM) from 1 assay(s)
Binding MOAD:  2WF1 IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.184 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.177α = 90
b = 77.001β = 90
c = 104.237γ = 90
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2009-05-19
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-03-06
    Changes: Data collection, Experimental preparation, Other
  • Version 1.4: 2019-05-15
    Changes: Data collection, Experimental preparation