2Y82

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure and Property Based Design of Factor Xa Inhibitors: Pyrrolidin-2-Ones with Aminoindane and Phenylpyrrolidine P4 Motifs.

Young, R.J.Adams, C.Blows, M.Brown, D.Burns-Kurtis, C.L.Chan, C.Chaudry, L.Convery, M.A.Davies, D.E.Exall, A.M.Foster, G.Harling, J.D.Hortense, E.Irvine, S.Irving, W.R.Jackson, S.Kleanthous, S.Pateman, A.J.Patikis, A.N.Roethka, T.J.Senger, S.Stelman, G.J.Toomey, J.R.West, R.I.Whittaker, C.Zhou, P.Watson, N.S.

(2011) Bioorg Med Chem Lett 21: 1582

  • DOI: https://doi.org/10.1016/j.bmcl.2011.01.131
  • Primary Citation of Related Structures:  
    2Y7Z, 2Y80, 2Y81, 2Y82

  • PubMed Abstract: 

    The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.


  • Organizational Affiliation

    GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom. Rob.J.Young@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACTIVATED FACTOR XA HEAVY CHAIN254Homo sapiensMutation(s): 0 
EC: 3.4.21.6
UniProt & NIH Common Fund Data Resources
Find proteins for P00742 (Homo sapiens)
Explore P00742 
Go to UniProtKB:  P00742
PHAROS:  P00742
GTEx:  ENSG00000126218 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00742
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
FACTOR X LIGHT CHAIN134Homo sapiensMutation(s): 0 
EC: 3.4.21.6
UniProt & NIH Common Fund Data Resources
Find proteins for P00742 (Homo sapiens)
Explore P00742 
Go to UniProtKB:  P00742
PHAROS:  P00742
GTEx:  ENSG00000126218 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00742
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
930
Query on 930

Download Ideal Coordinates CCD File 
C [auth A]6-CHLORO-N-((3S)-2-OXO-1-{4-[(2S)-2-PYRROLIDINYL]PHENYL}-3-PYRROLIDINYL)-2-NAPHTHALENESULFONAMIDE
C24 H23 Cl F N3 O3 S
OKMBULRSJZKGQF-VXKWHMMOSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
D [auth A]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
930 Binding MOAD:  2Y82 Ki: 4 (nM) from 1 assay(s)
PDBBind:  2Y82 Ki: 4 (nM) from 1 assay(s)
BindingDB:  2Y82 Ki: min: 2, max: 4 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.181 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.693α = 90
b = 72.212β = 90
c = 78.759γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-03-16
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-10-16
    Changes: Data collection, Experimental preparation, Other