3O1G

Cathepsin K covalently bound to a 2-cyano pyrimidine inhibitor with a benzyl P3 group.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.

Rankovic, Z.Cai, J.Kerr, J.Fradera, X.Robinson, J.Mistry, A.Finlay, W.McGarry, G.Andrews, F.Caulfield, W.Cumming, I.Dempster, M.Waller, J.Arbuckle, W.Anderson, M.Martin, I.Mitchell, A.Long, C.Baugh, M.Westwood, P.Kinghorn, E.Jones, P.Uitdehaag, J.C.van Zeeland, M.Potin, D.Saniere, L.Fouquet, A.Chevallier, F.Deronzier, H.Dorleans, C.Nicolai, E.

(2010) Bioorg Med Chem Lett 20: 6237-6241

  • DOI: https://doi.org/10.1016/j.bmcl.2010.08.101
  • Primary Citation of Related Structures:  
    3O0U, 3O1G

  • PubMed Abstract: 

    Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.


  • Organizational Affiliation

    Merck Research Laboratories, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, United Kingdom. zoran.rankovic@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cathepsin K215Homo sapiensMutation(s): 0 
Gene Names: CTSKCTSOCTSO2
EC: 3.4.22.38
UniProt & NIH Common Fund Data Resources
Find proteins for P43235 (Homo sapiens)
Explore P43235 
Go to UniProtKB:  P43235
PHAROS:  P43235
GTEx:  ENSG00000143387 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43235
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
O75
Query on O75

Download Ideal Coordinates CCD File 
D [auth A]N-benzyl-3-(2-cyano-6-propylpyrimidin-4-yl)-N-[2-(dimethylamino)ethyl]-5-(trifluoromethyl)benzamide
C27 H28 F3 N5 O
AGGVJWZHDDIPAU-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
O75 PDBBind:  3O1G IC50: 1 (nM) from 1 assay(s)
BindingDB:  3O1G IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.198 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.170 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.504α = 90
b = 62.504β = 90
c = 113.478γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
CrystalCleardata reduction
SCALAdata 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: 2010-10-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance