2VNN

Human BACE-1 in complex with 7-ethyl-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((3-(trifluoromethyl)phenyl)methyl)amino)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: 1.87 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Second Generation of Hydroxyethylamine Bace-1 Inhibitors: Optimizing Potency and Oral Bioavailability.

Charrier, N.Clarke, B.Cutler, L.Demont, E.Dingwall, C.Dunsdon, R.East, P.Hawkins, J.Howes, C.Hussain, I.Jeffrey, P.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.

(2008) J Med Chem 51: 3313

  • DOI: https://doi.org/10.1021/jm800138h
  • Primary Citation of Related Structures:  
    2VNM, 2VNN

  • PubMed Abstract: 

    BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.


  • Organizational Affiliation

    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Park, Harlow, Essex, UK.


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
CM7
Query on CM7

Download Ideal Coordinates CCD File 
B [auth A]N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]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 H35 F3 N4 O4 S
MSHYGGHZTGSTOG-LMSSTIIKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CM7 Binding MOAD:  2VNN IC50: 2 (nM) from 1 assay(s)
BindingDB:  2VNN IC50: 2 (nM) from 1 assay(s)
PDBBind:  2VNN IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.469α = 90
b = 76.699β = 90
c = 104.174γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
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: 2008-05-20
    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: 2019-04-03
    Changes: Data collection, Source and taxonomy
  • Version 1.5: 2019-05-15
    Changes: Data collection, Experimental preparation