1V3X

Factor Xa in complex with the inhibitor 1-[6-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridin-2-yl] carbonyl-2-carbamoyl-4-(6-chloronaphth-2-ylsulphonyl)piperazine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Synthesis and conformational analysis of a non-amidine factor Xa inhibitor that incorporates 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine as S4 binding element

Haginoya, N.Kobayashi, S.Komoriya, S.Yoshino, T.Suzuki, M.Shimada, T.Watanabe, K.Hirokawa, Y.Furugori, T.Nagahara, T.

(2004) J Med Chem 47: 5167-5182

  • DOI: https://doi.org/10.1021/jm049884d
  • Primary Citation of Related Structures:  
    1V3X

  • PubMed Abstract: 

    Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expected to be S4 binding element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine type 61 displayed orally potent anti-fXa activity and evident prolongation of prothrombin time (PT) with the moderate bioavailability in rats. The X-ray crystal analysis afforded an obvious binding mode that 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a novel intramolecular S-O close contact. Ab initio energy calculations of model compounds deduced that conformers with the most close S-O proximity were most stable. The Mulliken population analysis proposed that this energy profile was caused by both of electrostatic S-O affinity and N-O repulsion. The results of these calculations and X-ray analysis suggested a possibility that the restricted conformation effected the affinity to S4 subsite of fXa.


  • Organizational Affiliation

    Medicinal Chemistry Research Laboratory, Discovery Research Laboratory, Drug Metabolism & Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co. Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. hagin9kg@daiichipharm.co.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor X, HEAVY CHAIN233Homo 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
Coagulation factor X, LIGHT CHAIN52Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
D76
Query on D76

Download Ideal Coordinates CCD File 
E [auth A](2R)-4-[(6-CHLORO-2-NAPHTHYL)SULFONYL]-1-[(5-METHYL-4,5,6,7-TETRAHYDRO[1,3]THIAZOLO[5,4-C]PYRIDIN-2-YL)CARBONYL]PIPERAZ INE-2-CARBOXAMIDE
C23 H24 Cl N5 O4 S2
OVHHNKPYYVQCLN-LJQANCHMSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
D76 PDBBind:  1V3X IC50: 24 (nM) from 1 assay(s)
BindingDB:  1V3X IC50: 24 (nM) from 1 assay(s)
Binding MOAD:  1V3X IC50: 24 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.05α = 90
b = 71.927β = 90
c = 78.799γ = 90
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
REFMACrefinement
CCP4data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2004-11-07 
  • Deposition Author(s): Suzuki, M.

Revision History  (Full details and data files)

  • Version 1.0: 2004-11-07
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-10-25
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary