3IGB

Bace-1 with Compound 3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors

Malamas, M.S.Erdei, J.Gunawan, I.Barnes, K.Johnson, M.Hui, Y.Turner, J.Hu, Y.Wagner, E.Fan, K.Olland, A.Bard, J.Robichaud, A.J.

(2009) J Med Chem 52: 6314-6323

  • DOI: https://doi.org/10.1021/jm9006752
  • Primary Citation of Related Structures:  
    3IGB

  • PubMed Abstract: 

    The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and >100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma Abeta40 measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).


  • Organizational Affiliation

    Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543-8000, USA. malamam@wyeth.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1415Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
454
Query on 454

Download Ideal Coordinates CCD File 
B [auth A]8,8-diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine
C18 H18 N4
UFWSJOVQEPTPNE-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
454 BindingDB:  3IGB IC50: min: 2.70e+4, max: 3.80e+4 (nM) from 2 assay(s)
EC50: 1.60e+4 (nM) from 1 assay(s)
Binding MOAD:  3IGB IC50: 3.80e+4 (nM) from 1 assay(s)
PDBBind:  3IGB IC50: 3.80e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.137α = 90
b = 104.33β = 94.69
c = 49.551γ = 90
Software Package:
Software NamePurpose
AMoREphasing
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-11-03 
  • Deposition Author(s): Olland, A.M.

Revision History  (Full details and data files)

  • Version 1.0: 2009-11-03
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description