3OOZ

Bace1 in complex with the aminohydantoin Compound 102


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.217 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Design and Synthesis of Aminohydantoins as Potent and Selective Human beta-Secretase (BACE1) Inhibitors with Enhanced Brain Permeability

Malamas, M.S.Robichaud, A.Erdei, J.Quagliato, D.Solvibile, W.Zhou, P.Morris, K.Turner, J.Wagner, E.Fan, K.Olland, A.Jacobsen, S.Reinhart, P.Riddell, D.Pangalos, M.

(2010) Bioorg Med Chem Lett 20: 6597-6605

  • DOI: https://doi.org/10.1016/j.bmcl.2010.09.029
  • Primary Citation of Related Structures:  
    3OOZ

  • PubMed Abstract: 

    The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o..


  • Organizational Affiliation

    Department of Chemical Sciences, Pfizer, CN 8000, Princeton, NJ 08543-8000, USA. malamas.michael@gmail.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
ZOO
Query on ZOO

Download Ideal Coordinates CCD File 
B [auth A](5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(5-fluoropent-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
C22 H19 F4 N3 O2
ZSIZOKHLIKKQIV-JOCHJYFZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ZOO BindingDB:  3OOZ IC50: 32 (nM) from 1 assay(s)
Binding MOAD:  3OOZ IC50: 14 (nM) from 1 assay(s)
PDBBind:  3OOZ IC50: 14 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.217 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.927α = 90
b = 104.664β = 94.91
c = 50.54γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2011-08-31 
  • Deposition Author(s): Olland, A.M.

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-31
    Type: Initial release
  • Version 1.1: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description