4R8Y

BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((R)-1-(2-cyclopentylacetyl)pyrrolidin-3-yl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of potent iminoheterocycle BACE1 inhibitors.

Caldwell, J.P.Mazzola, R.D.Durkin, J.Chen, J.Chen, X.Favreau, L.Kennedy, M.Kuvelkar, R.Lee, J.McHugh, N.McKittrick, B.Orth, P.Stamford, A.Strickland, C.Voigt, J.Wang, L.Zhang, L.Zhang, Q.Zhu, Z.

(2014) Bioorg Med Chem Lett 24: 5455-5459

  • DOI: https://doi.org/10.1016/j.bmcl.2014.10.006
  • Primary Citation of Related Structures:  
    4R8Y, 4R91, 4R92, 4R93, 4R95

  • PubMed Abstract: 

    The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aβ40 levels upon subcutaneous and oral administration to rats.


  • Organizational Affiliation

    Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: john.caldwell@merck.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: 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3KO
Query on 3KO

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
(2E,5R)-5-(2-cyclohexylethyl)-5-{[(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]methyl}-2-imino-3-methylimidazolidin-4-one
C24 H40 N4 O2
ZROUWOKUKKGJPH-HYBUGGRVSA-N
TLA
Query on TLA

Download Ideal Coordinates CCD File 
D [auth B]L(+)-TARTARIC ACID
C4 H6 O6
FEWJPZIEWOKRBE-JCYAYHJZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3KO Binding MOAD:  4R8Y Ki: 640 (nM) from 1 assay(s)
BindingDB:  4R8Y Ki: 640 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.4α = 90
b = 89.43β = 90
c = 131γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
SCALEPACKdata scaling
PDB_EXTRACTdata extraction
ADSCdata collection
DENZOdata reduction
CNSphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-11-05
    Type: Initial release
  • Version 1.1: 2014-12-17
    Changes: Database references