5I3X

Crystal structure of BACE1 in complex with aminoquinoline inhibitor 6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of beta-Secretase.

Jordan, J.B.Whittington, D.A.Bartberger, M.D.Sickmier, E.A.Chen, K.Cheng, Y.Judd, T.

(2016) J Med Chem 59: 3732-3749

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01917
  • Primary Citation of Related Structures:  
    5I3V, 5I3W, 5I3X, 5I3Y, 5IE1

  • PubMed Abstract: 

    Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with (19)F NMR-based methods has been shown to provide several advantages over (1)H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of (19)F-based fragment screening by detailing the identification of a second-site fragment through (19)F NMR screening that binds to a specific pocket of the aspartic acid protease, β-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment-linking approach, which ultimately yielded a molecule exhibiting a more than 360-fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling.


  • Organizational Affiliation

    Therapeutic Discovery, Amgen, Inc. One Amgen Center Drive, Thousand Oaks, California 91320, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1411Homo sapiensMutation(s): 2 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
68J
Query on 68J

Download Ideal Coordinates CCD File 
B [auth A]N-(1-{3-[2-(2-amino-3-{3-[(3,3-dimethylbutyl)amino]-3-oxopropyl}quinolin-6-yl)phenyl]prop-2-yn-1-yl}cyclopropyl)-4-fluorobenzamide
C37 H39 F N4 O2
QLQWEADMFLXRFH-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
68J BindingDB:  5I3X Kd: 8 (nM) from 1 assay(s)
IC50: min: 9, max: 191 (nM) from 2 assay(s)
Binding MOAD:  5I3X Kd: 8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.59α = 90
b = 101.59β = 90
c = 174.626γ = 120
Software Package:
Software NamePurpose
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-30
    Type: Initial release
  • Version 1.1: 2016-04-20
    Changes: Database references
  • Version 1.2: 2016-05-11
    Changes: Database references
  • Version 1.3: 2017-11-01
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description