3RSV

Structure of Bace-1 (Beta-Secretase) in complex with (R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpropanamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1).

Cheng, Y.Judd, T.C.Bartberger, M.D.Brown, J.Chen, K.Fremeau, R.T.Hickman, D.Hitchcock, S.A.Jordan, B.Li, V.Lopez, P.Louie, S.W.Luo, Y.Michelsen, K.Nixey, T.Powers, T.S.Rattan, C.Sickmier, E.A.St Jean, D.J.Wahl, R.C.Wen, P.H.Wood, S.

(2011) J Med Chem 54: 5836-5857

  • DOI: https://doi.org/10.1021/jm200544q
  • Primary Citation of Related Structures:  
    3RSV, 3RSX, 3RTH, 3RTM, 3RTN, 3RU1, 3RVI

  • PubMed Abstract: 

    Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 μM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC(50) value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Aβ levels in cerebrospinal fluid (CSF).


  • Organizational Affiliation

    Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. yuanc@amgen.com


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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3RS
Query on 3RS

Download Ideal Coordinates CCD File 
I [auth A](2R)-3-[2-amino-6-(2-methylphenyl)quinolin-3-yl]-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-methylpropanamide
C27 H33 N3 O2
QMSHBBGXSXAGOO-XMSQKQJNSA-N
IOD
Query on IOD

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A],
D [auth A],
E [auth A]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
H [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3RS Binding MOAD:  3RSV IC50: 0.7 (nM) from 1 assay(s)
BindingDB:  3RSV IC50: min: 0.7, max: 18 (nM) from 2 assay(s)
PDBBind:  3RSV IC50: 0.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.42α = 90
b = 103.42β = 90
c = 169.535γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data 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: 2011-08-31
    Type: Initial release
  • Version 1.1: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description