4DH6

Structure of Bace-1 (Beta-Secretase) in Complex with (2R)-N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4-((S)-6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridine]-4'-ylamino)butan-2-yl)-2-methoxypropanamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.231 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Design and preparation of a potent series of hydroxyethylamine containing beta-secretase inhibitors that demonstrate robust reduction of central beta-amyloid.

Weiss, M.M.Williamson, T.Babu-Khan, S.Bartberger, M.D.Brown, J.Chen, K.Cheng, Y.Citron, M.Croghan, M.D.Dineen, T.A.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.Rattan, C.San Miguel, T.Sickmier, E.A.Wahl, R.C.Wen, P.H.Wood, S.Xue, Q.Yang, B.H.Patel, V.F.Zhong, W.

(2012) J Med Chem 55: 9009-9024

  • DOI: https://doi.org/10.1021/jm300119p
  • Primary Citation of Related Structures:  
    4DH6

  • PubMed Abstract: 

    A series of potent hydroxyethyl amine (HEA) derived inhibitors of β-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS β-amyloid (Aβ) in Sprague-Dawley rats following oral administration.


  • Organizational Affiliation

    Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States. mmweiss@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1411Homo sapiensMutation(s): 2 
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
0KN
Query on 0KN

Download Ideal Coordinates CCD File 
L [auth A](2R)-N-[(2S,3R)-1-(1,3-benzodioxol-5-yl)-4-{[(4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl]amino}-3-hydroxybutan-2-yl]-2-methoxypropanamide
C31 H43 N3 O6
OMMVFRZSBCRMQD-LJYZBVLISA-N
IOD
Query on IOD

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
GOL
Query on GOL

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0KN BindingDB:  4DH6 IC50: min: 14, max: 26 (nM) from 4 assay(s)
PDBBind:  4DH6 IC50: 16.8 (nM) from 1 assay(s)
Binding MOAD:  4DH6 IC50: 16.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.231 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.694α = 90
b = 103.694β = 90
c = 168.866γ = 120
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-04-18
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references