3L3A

Bace-1 with the aminopyridine Compound 32


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.36 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.

Malamas, M.S.Barnes, K.Hui, Y.Johnson, M.Lovering, F.Condon, J.Fobare, W.Solvibile, W.Turner, J.Hu, Y.Manas, E.S.Fan, K.Olland, A.Chopra, R.Bard, J.Pangalos, M.N.Reinhart, P.Robichaud, A.J.

(2010) Bioorg Med Chem Lett 20: 2068-2073

  • DOI: https://doi.org/10.1016/j.bmcl.2010.02.075
  • Primary Citation of Related Structures:  
    3L38, 3L3A

  • PubMed Abstract: 

    The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood-brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.


  • Organizational Affiliation

    Department of Chemical Sciences, Wyeth, 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
625
Query on 625

Download Ideal Coordinates CCD File 
B [auth A]4-(4-{1-[(6-aminopyridin-2-yl)methyl]-5-(2-chlorophenyl)-1H-pyrrol-2-yl}phenoxy)butanenitrile
C26 H23 Cl N4 O
CERJQPWNRISSQS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
625 Binding MOAD:  3L3A IC50: 420 (nM) from 1 assay(s)
BindingDB:  3L3A IC50: 420 (nM) from 1 assay(s)
PDBBind:  3L3A IC50: 420 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.36 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.227α = 90
b = 103.252β = 94.88
c = 49.784γ = 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: 2010-04-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance