3INH

Bace1 with the aminohydantoin Compound R-58


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.211 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors.

Malamas, M.S.Erdei, J.Gunawan, I.Turner, J.Hu, Y.Wagner, E.Fan, K.Chopra, R.Olland, A.Bard, J.Jacobsen, S.Magolda, R.L.Pangalos, M.Robichaud, A.J.

(2010) J Med Chem 53: 1146-1158

  • DOI: https://doi.org/10.1021/jm901414e
  • Primary Citation of Related Structures:  
    3IND, 3INE, 3INF, 3INH

  • PubMed Abstract: 

    The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (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
569
Query on 569

Download Ideal Coordinates CCD File 
B [auth A](5R)-2-amino-5-(4-fluoro-3-pyrimidin-5-ylphenyl)-3-methyl-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one
C21 H15 F4 N5 O2
RNJTYVPMRSKRKE-HXUWFJFHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
569 Binding MOAD:  3INH IC50: 20 (nM) from 1 assay(s)
PDBBind:  3INH IC50: 20 (nM) from 1 assay(s)
BindingDB:  3INH IC50: min: 20, max: 40 (nM) from 2 assay(s)
EC50: min: 20, max: 270 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.211 
  • 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
HKL-2000data collection
AMoREphasing
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-03-02
    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