5KQF

(4~{S},6~{S})-4-[2,4-bis(fluoranyl)phenyl]-4-methyl-6-pyrimidin-5-yl-5,6-dihydro-1,3-thiazin-2-amine (compound 12) bound to BACE1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine beta-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.

Wu, Y.J.Guernon, J.Shi, J.Marcin, L.Higgins, M.Rajamani, R.Muckelbauer, J.Lewis, H.Chang, C.Camac, D.Toyn, J.H.Ahlijanian, M.K.Albright, C.F.Macor, J.E.Thompson, L.A.

(2016) J Med Chem 59: 8593-8600

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01012
  • Primary Citation of Related Structures:  
    5KQF, 5KR8

  • PubMed Abstract: 

    Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aβ reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.


  • Organizational Affiliation

    Research and Development, Bristol-Myers Squibb Company , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1455Homo 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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6WD
Query on 6WD

Download Ideal Coordinates CCD File 
B [auth A](4~{S},6~{S})-4-[2,4-bis(fluoranyl)phenyl]-4-methyl-6-pyrimidin-5-yl-5,6-dihydro-1,3-thiazin-2-amine
C15 H14 F2 N4 S
AHFBBIPUKVCJEP-ZFWWWQNUSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6WD Binding MOAD:  5KQF IC50: 310 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.223 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.158α = 90
b = 102.158β = 90
c = 169.78γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-07
    Type: Initial release
  • Version 1.1: 2016-10-05
    Changes: Database references