2WF0

Human BACE-1 in complex with 4-ethyl-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((3-(trifluoromethyl)phenyl)methyl)amino)propyl)-8-(2-oxo-1-pyrrolidinyl)-6-quinolinecarboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.188 

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 1: The Need for Improved Pharmacokinetics.

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: 3664

  • DOI: https://doi.org/10.1016/j.bmcl.2009.03.165
  • Primary Citation of Related Structures:  
    2WEZ, 2WF0

  • PubMed Abstract: 

    Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.


  • 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
ZY0
Query on ZY0

Download Ideal Coordinates CCD File 
B [auth A]N-[(1S,2R)-1-BENZYL-2-HYDROXY-3-{[3-(TRIFLUOROMETHYL)BENZYL]AMINO}PROPYL]-4-ETHYL-8-(2-OXOPYRROLIDIN-1-YL)QUINOLINE-6-CARBOXAMIDE
C34 H35 F3 N4 O3
YDNCUOPJVVQEMT-MFMCTBQISA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ZY0 Binding MOAD:  2WF0 IC50: 210 (nM) from 1 assay(s)
BindingDB:  2WF0 IC50: 210 (nM) from 1 assay(s)
PDBBind:  2WF0 IC50: 210 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.188 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.368α = 90
b = 76.715β = 90
c = 104.183γ = 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