3H0B

Discovery of aminoheterocycles as a novel beta-secretase inhibitor class


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1.

Stachel, S.J.Coburn, C.A.Rush, D.Jones, K.L.Zhu, H.Rajapakse, H.Graham, S.L.Simon, A.Katharine Holloway, M.Allison, T.J.Munshi, S.K.Espeseth, A.S.Zuck, P.Colussi, D.Wolfe, A.Pietrak, B.L.Lai, M.T.Vacca, J.P.

(2009) Bioorg Med Chem Lett 19: 2977-2980

  • DOI: https://doi.org/10.1016/j.bmcl.2009.04.033
  • Primary Citation of Related Structures:  
    3H0B

  • PubMed Abstract: 

    We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA. shawn_stachel@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
405Homo sapiensMutation(s): 0 
Gene Names: BACEBACE1beta-secretaseKIAA1149
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
B35
Query on B35

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
4-[(1S)-1-(3-fluoro-4-methoxyphenyl)-2-(2-methoxy-5-nitrophenyl)ethyl]-1H-imidazol-2-amine
C19 H19 F N4 O4
RFLOFHKRBGKCOB-AWEZNQCLSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
B35 PDBBind:  3H0B IC50: 3200 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 221.178α = 90
b = 107.44β = 99.47
c = 65.084γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-07
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description