Selective binding of coumarin enantiomers to human alpha1-acid glycoprotein genetic variants.
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.
Hazai
Eszter
E
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, PO Box 17, H-1525 Budapest, Hungary. hazaie@chemres.hu
Visy
Júlia
J
Fitos
Ilona
I
Bikádi
Zsolt
Z
Simonyi
Miklós
M
D000074:Acenocoumarol / Q000737:chemistry / Q000378:metabolism; D000925:Anticoagulants / Q000737:chemistry / Q000378:metabolism; D003374:Coumarins / Q000737:chemistry* / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D009961:Orosomucoid / Q000235:genetics / Q000378:metabolism*; D010644:Phenprocoumon / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011798:Quinaldines / Q000737:chemistry; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism
D000925:Anticoagulants; D003374:Coumarins; D008024:Ligands; D009961:Orosomucoid; D011798:Quinaldines; D014859:Warfarin; C037073:2-methylquinoline; D000074:Acenocoumarol; D010644:Phenprocoumon