3VF3

Crystal Structure of Human Beta Secretase in Complex with NVP-BQQ711


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.48 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Discovery of cyclic sulfone hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides

Rueeger, H.Lueoend, R.Rogel, O.Rondeau, J.M.Mobitz, H.Machauer, R.Jacobson, L.Staufenbiel, M.Desrayaud, S.Neumann, U.

(2012) J Med Chem 55: 3364-3386

  • DOI: https://doi.org/10.1021/jm300069y
  • Primary Citation of Related Structures:  
    3VEU, 3VF3, 3VG1, 4D83, 4D85, 4D88, 4D89, 4D8C

  • PubMed Abstract: 

    Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.


  • Organizational Affiliation

    Department of Global Discovery Chemistry, Institutes for BioMedical Research, Novartis Pharma AG, CH-4057 Basel, Switzerland. heinrich.rueeger@novartis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1402Homo sapiensMutation(s): 0 
Gene Names: BACE1
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
0GS
Query on 0GS

Download Ideal Coordinates CCD File 
B [auth A](3S,4S,5R)-3-(4-amino-3-bromo-5-fluorobenzyl)-5-{[3-(1,1-difluoroethyl)benzyl]amino}tetrahydro-2H-thiopyran-4-ol 1,1-dioxide
C21 H24 Br F3 N2 O3 S
QBRKIXCNLLQOPH-WNYOCNMUSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0GS Binding MOAD:  3VF3 IC50: 1370 (nM) from 1 assay(s)
BindingDB:  3VF3 IC50: min: 1370, max: 4980 (nM) from 2 assay(s)
PDBBind:  3VF3 IC50: 1370 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.48 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.185 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.984α = 90
b = 74.653β = 90
c = 104.435γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
CNXphasing
CNXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-21
    Type: Initial release