4DI2

Crystal structure of BACE1 in complex with hydroxyethylamine inhibitor 37


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Design and synthesis of potent, orally efficacious hydroxyethylamine derived beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.

Dineen, T.A.Weiss, M.M.Williamson, T.Acton, P.Babu-Khan, S.Bartberger, M.D.Brown, J.Chen, K.Cheng, Y.Citron, M.Croghan, M.D.Dunn, R.T.Esmay, J.Graceffa, R.F.Harried, S.S.Hickman, D.Hitchcock, S.A.Horne, D.B.Huang, H.Imbeah-Ampiah, R.Judd, T.Kaller, M.R.Kreiman, C.R.La, D.S.Li, V.Lopez, P.Louie, S.Monenschein, H.Nguyen, T.T.Pennington, L.D.San Miguel, T.Sickmier, E.A.Vargas, H.M.Wahl, R.C.Wen, P.H.Whittington, D.A.Wood, S.Xue, Q.Yang, B.H.Patel, V.F.Zhong, W.

(2012) J Med Chem 55: 9025-9044

  • DOI: https://doi.org/10.1021/jm300118s
  • Primary Citation of Related Structures:  
    4DI2

  • PubMed Abstract: 

    We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-β peptide (Aβ) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Aβ levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.


  • Organizational Affiliation

    Chemical Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States. tdineen@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
411Homo sapiensMutation(s): 2 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0K9
Query on 0K9

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B],
J [auth C]
(2R)-N-{(2S,3R)-4-{[(4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl]amino}-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl}-2-methoxypropanamide
C33 H44 N4 O4 S
IUSARDYWEPUTPN-OZBXUNDUSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
H [auth B],
I [auth B],
K [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0K9 PDBBind:  4DI2 IC50: 5.5 (nM) from 1 assay(s)
Binding MOAD:  4DI2 IC50: 5.5 (nM) from 1 assay(s)
BindingDB:  4DI2 IC50: min: 5.5, max: 9.9 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.704α = 90
b = 104.765β = 103.87
c = 101.557γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-10
    Type: Initial release
  • Version 1.1: 2013-06-19
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description