2Q15

Structure of BACE complexed to compound 3a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.344 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.256 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-Site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.

Baxter, E.W.Conway, K.A.Kennis, L.Bischoff, F.Mercken, M.H.Winter, H.L.Reynolds, C.H.Tounge, B.A.Luo, C.Scott, M.K.Huang, Y.Braeken, M.Pieters, S.M.Berthelot, D.J.Masure, S.Bruinzeel, W.D.Jordan, A.D.Parker, M.H.Boyd, R.E.Qu, J.Alexander, R.S.Brenneman, D.E.Reitz, A.B.

(2007) J Med Chem 50: 4261-4264

  • DOI: https://doi.org/10.1021/jm0705408
  • Primary Citation of Related Structures:  
    2Q11, 2Q15

  • PubMed Abstract: 

    A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.


  • Organizational Affiliation

    Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pennsylvania 19477, USA. ebaxter@prdus.jnj.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1385Homo sapiensMutation(s): 4 
Gene Names: BACE1BACE
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
3MR
Query on 3MR

Download Ideal Coordinates CCD File 
B [auth A](4S)-4-(2-AMINO-6-PHENOXYQUINAZOLIN-3(4H)-YL)-N,4-DICYCLOHEXYL-N-METHYLBUTANAMIDE
C31 H42 N4 O2
JKQCQYBXDQPJNC-LJAQVGFWSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3MR BindingDB:  2Q15 Ki: min: 8, max: 30 (nM) from 4 assay(s)
Binding MOAD:  2Q15 Ki: 11 (nM) from 1 assay(s)
PDBBind:  2Q15 Ki: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.344 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.256 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.347α = 90
b = 102.347β = 90
c = 169.715γ = 120
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2007-08-14 
  • Deposition Author(s): Sharff, A.J.

Revision History  (Full details and data files)

  • Version 1.0: 2007-08-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations