2WF4

Human BACE-1 in complex with 6-ethyl-1-methyl-N-((1S)-2-oxo-1-(phenylmethyl)-3-(tetrahydro-2H-pyran-4-ylamino)propyl)-1,3,4,6- tetrahydro(1,2)thiazepino(5,4,3-cd)indole-8-carboxamide 2,2-dioxide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 

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 3: Towards Non Hydroxyethylamine Transition State Mimetics.

Charrier, N.Clarke, B.Cutler, L.Demont, E.Dingwall, C.Dunsdon, R.Hawkins, J.Howes, C.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: 3674

  • DOI: https://doi.org/10.1016/j.bmcl.2009.03.149
  • Primary Citation of Related Structures:  
    2WF4

  • PubMed Abstract: 

    Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.


  • 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
ZY4
Query on ZY4

Download Ideal Coordinates CCD File 
B [auth A]N-[(1S)-1-BENZYL-2,2-DIHYDROXY-3-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)PROPYL]-6-ETHYL-1-METHYL-1,3,4,6-TETRAHYDRO[1,2]THIAZEPINO[5,4,3-CD]INDOLE-8-CARBOXAMIDE 2,2-DIOXIDE
C29 H38 N4 O6 S
LMEDJLLRHRUTJN-SANMLTNESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ZY4 PDBBind:  2WF4 IC50: 13 (nM) from 1 assay(s)
Binding MOAD:  2WF4 IC50: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.52α = 90
b = 76.626β = 90
c = 104.737γ = 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: 2009-05-12
    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