3VG1

Crystal Structure of Human Beta Secretase in Complex with NVP-BUR436, derived from a soaking experiment


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


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: BACEBACE1KIAA1149
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
0GT
Query on 0GT

Download Ideal Coordinates CCD File 
B [auth A](3R,4S,5S)-3-[(3-tert-butylbenzyl)amino]-5-{[3-(2,2-difluoroethyl)-1H-indol-5-yl]methyl}tetrahydro-2H-thiopyran-4-ol 1,1-dioxide
C27 H34 F2 N2 O3 S
OOZZVYSXZBAROL-PSUQPPDWSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0GT Binding MOAD:  3VG1 IC50: 55 (nM) from 1 assay(s)
BindingDB:  3VG1 IC50: min: 55, max: 7420 (nM) from 2 assay(s)
PDBBind:  3VG1 IC50: 55 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.702α = 90
b = 72.239β = 90
c = 104.585γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
CNXphasing
CNXrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

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