3IVI

Design and Synthesis of Potent BACE-1 Inhibitors with Cellular Activity: Structure-Activity Relationship of P1 Substituents


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.

Sealy, J.M.Truong, A.P.Tso, L.Probst, G.D.Aquino, J.Hom, R.K.Jagodzinska, B.M.Dressen, D.Wone, D.W.Brogley, L.John, V.Tung, J.S.Pleiss, M.A.Tucker, J.A.Konradi, A.W.Dappen, M.S.Toth, G.Pan, H.Ruslim, L.Miller, J.Bova, M.P.Sinha, S.Quinn, K.P.Sauer, J.M.

(2009) Bioorg Med Chem Lett 19: 6386-6391

  • DOI: https://doi.org/10.1016/j.bmcl.2009.09.061
  • Primary Citation of Related Structures:  
    3IVH, 3IVI

  • PubMed Abstract: 

    Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
406Homo sapiensMutation(s): 0 
Gene Names: BACE1BACEKIAA1149
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2LI
Query on 2LI

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B],
O [auth C]
N-[(1S,2R)-3-{[(5S)-5-(3-tert-butylphenyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide
C29 H36 F2 N4 O2
BAILJXDQIBWAPX-GKRYNVPLSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
H [auth B]
I [auth B]
L [auth C]
D [auth A],
E [auth A],
H [auth B],
I [auth B],
L [auth C],
M [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
N [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2LI Binding MOAD:  3IVI IC50: 12 (nM) from 1 assay(s)
PDBBind:  3IVI IC50: 12 (nM) from 1 assay(s)
BindingDB:  3IVI IC50: 12 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.711α = 90
b = 104.48β = 104.83
c = 100.616γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2010-01-05 
  • Deposition Author(s): Pan, H.

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-05
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Refinement description, Version format compliance