4I10

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.

Bowers, S.Xu, Y.Z.Yuan, S.Probst, G.D.Hom, R.K.Chan, W.Konradi, A.W.Sham, H.L.Zhu, Y.L.Beroza, P.Pan, H.Brecht, E.Yao, N.Lougheed, J.Tam, D.Ren, Z.Ruslim, L.Bova, M.P.Artis, D.R.

(2013) Bioorg Med Chem Lett 23: 2181-2186

  • DOI: https://doi.org/10.1016/j.bmcl.2013.01.103
  • Primary Citation of Related Structures:  
    4HZT, 4I0G, 4I0Z, 4I10, 4I11

  • PubMed Abstract: 

    The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.


  • Organizational Affiliation

    Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA. simeongbowers@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1406Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
1BS PDBBind:  4I10 IC50: 170 (nM) from 1 assay(s)
Binding MOAD:  4I10 IC50: 170 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.172 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.09α = 90
b = 103.9β = 90
c = 99.72γ = 90
Software Package:
Software NamePurpose
StructureStudiodata collection
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-03-06
    Type: Initial release
  • Version 1.1: 2013-04-24
    Changes: Database references