3IN3

Bace1 with Compound 30


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Di-substituted pyridinyl aminohydantoins as potent and highly selective human beta-secretase (BACE1) inhibitors.

Malamas, M.S.Barnes, K.Johnson, M.Hui, Y.Zhou, P.Turner, J.Hu, Y.Wagner, E.Fan, K.Chopra, R.Olland, A.Bard, J.Pangalos, M.Reinhart, P.Robichaud, A.J.

(2010) Bioorg Med Chem 18: 630-639

  • DOI: https://doi.org/10.1016/j.bmc.2009.12.007
  • Primary Citation of Related Structures:  
    3IN3, 3IN4

  • PubMed Abstract: 

    The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as beta-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500x) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2' pocket (BACE1 Pro(70) changed to BACE2 Lys(86)) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC(50) value for BACE1 of 10nM, and exhibited cellular activity with an EC(50) value of 130nM in the ELISA assay.


  • Organizational Affiliation

    Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 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
472
Query on 472

Download Ideal Coordinates CCD File 
B [auth A](5S)-2-amino-3-methyl-5-pyridin-4-yl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-imidazol-4-one
C20 H17 N5 O
AIKOTXHNUIYVMD-HXUWFJFHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
472 Binding MOAD:  3IN3 IC50: 60 (nM) from 1 assay(s)
PDBBind:  3IN3 IC50: 60 (nM) from 1 assay(s)
BindingDB:  3IN3 IC50: 60 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.379α = 90
b = 104.854β = 94.79
c = 50.531γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
AMoREphasing
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2010-01-19 
  • Deposition Author(s): Olland, A.M.

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance