3L58

Structure of BACE Bound to SCH589432


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.201 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Discovery of Cyclic Acylguanidines as Highly Potent and Selective beta-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I-Inhibitor Design and Validation

Zhu, Z.Sun, Z.Y.Ye, Y.Voigt, J.Strickland, C.Smith, E.M.Cumming, J.Wang, L.Wong, J.Wang, Y.S.Wyss, D.F.Chen, X.Kuvelkar, R.Kennedy, M.E.Favreau, L.Parker, E.McKittrick, B.A.Stamford, A.Czarniecki, M.Greenlee, W.Hunter, J.C.

(2010) J Med Chem 53: 951-965

  • DOI: https://doi.org/10.1021/jm901408p
  • Primary Citation of Related Structures:  
    3L58, 3L59, 3L5B, 3L5C, 3L5D, 3L5E, 3L5F

  • PubMed Abstract: 

    A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. Zhaoning.Zhu@spcorp.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B
414Homo 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
CS5
Query on CS5

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N'-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-5-METHYL-N,N-DIPROPYLISOPHTHALAMIDE
C33 H41 F2 N3 O4
JEEOUWBWJFSMIP-IOWSJCHKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CS5 PDBBind:  3L58 IC50: 8 (nM) from 1 assay(s)
BindingDB:  3L58 IC50: min: 15, max: 80 (nM) from 4 assay(s)
Binding MOAD:  3L58 IC50: 8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.201 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.455α = 90
b = 89.34β = 90
c = 131.172γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-02-16
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description