3KMX

Structure of BACE bound to SCH346572


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Application of Fragment-Based NMR Screening, X-ray Crystallography, Structure-Based Design, and Focused Chemical Library Design to Identify Novel muM Leads for the Development of nM BACE-1 (beta-Site APP Cleaving Enzyme 1) Inhibitors.

Wang, Y.S.Strickland, C.Voigt, J.H.Kennedy, M.E.Beyer, B.M.Senior, M.M.Smith, E.M.Nechuta, T.L.Madison, V.S.Czarniecki, M.McKittrick, B.A.Stamford, A.W.Parker, E.M.Hunter, J.C.Greenlee, W.J.Wyss, D.F.

(2010) J Med Chem 53: 942-950

  • DOI: https://doi.org/10.1021/jm901472u
  • Primary Citation of Related Structures:  
    3KMX, 3KMY, 3KN0

  • PubMed Abstract: 

    Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper


  • Organizational Affiliation

    Schering-Plough Research Institute, 320 Bent Street, Cambridge, Massachusetts 02141, USA. allen.yu-sen.wang@spcorp.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B
395Homo sapiensMutation(s): 0 
Gene Names: BACEBACE1KIAA1149
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
G00
Query on G00

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-butoxy-3-chlorobenzyl imidothiocarbamate
C12 H17 Cl N2 O S
IONZMLSFEITLRK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
G00 BindingDB:  3KMX Kd: 15 (nM) from 1 assay(s)
IC50: min: 200, max: 210 (nM) from 2 assay(s)
PDBBind:  3KMX Kd: 1.50e+4 (nM) from 1 assay(s)
Binding MOAD:  3KMX Kd: 1.50e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.197 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.395α = 90
b = 89.335β = 90
c = 131.218γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
CNXphasing
CNXrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description