Selective binding of coumarin enantiomers to human α1-acid glycoprotein genetic variants

Eszter Hazai, J. Visy, I. Fitos, Zsolt Bikádi, M. Simonyi

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Coumarin-type anticoagulants, warfarin, phenprocoumon and acenocoumarol, were tested for their stereoselective binding to the human orosomucoid (ORM; AGP) genetic variants ORM 1 and ORM 2. Direct binding studies with racemic ligands were carried out by the ultrafiltration method; the concentrations of free enantiomers were determined by capillary electrophoresis. The binding of pure enantiomers was investigated with quinaldine red fluorescence displacement measurements. Our results demonstrated that all investigated compounds bind stronger to ORM 1 variant than to ORM 2. ORM 1 and human native AGP preferred the binding of (S)-enantiomers of warfarin and acenocoumarol, while no enantioselectivity was observed in phenprocoumon binding. Acenocoumarol possessed the highest enantioselectivity in AGP binding due to the weak binding of its (R)-enantiomer. Furthermore, a new homology model of AGP was built and the models of ORM 1 and ORM 2 suggested that difference in binding to AGP genetic variants is caused by steric factors.

Original languageEnglish
Pages (from-to)1959-1965
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number6
DOIs
Publication statusPublished - Mar 15 2006

Fingerprint

Acenocoumarol
Enantiomers
Phenprocoumon
Glycoproteins
Warfarin
Acids
Enantioselectivity
Orosomucoid
Ultrafiltration
Capillary Electrophoresis
Capillary electrophoresis
Anticoagulants
Displacement measurement
Fluorescence
Ligands
coumarin

Keywords

  • α- acid glycoprotein
  • Acenocoumarol
  • AGP
  • Capillary electrophoresis
  • CE, capillary electrophoresis
  • Displacement study
  • Genetic variants
  • Molecular modelling
  • ORM, orosomucoid
  • Phenprocoumon
  • QR, quinaldine red
  • Warfarin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Selective binding of coumarin enantiomers to human α1-acid glycoprotein genetic variants. / Hazai, Eszter; Visy, J.; Fitos, I.; Bikádi, Zsolt; Simonyi, M.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 6, 15.03.2006, p. 1959-1965.

Research output: Contribution to journalArticle

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