Selective binding interactions of deramciclane to the genetic variants of human alpha(1)-acid glycoprotein.
BACKGROUND
alpha(1)-Acid glycoprotein (AGP) plays a decisive role in the serum protein binding of several drugs.Genetic variants of AGP have different ligand binding properties. The binding of deramciclane (DER), a chiral anxiolytic agent, has been studied on A and F1/S genetic variants of AGP.


METHODS
The effects of DER and reference drugs on the binding of specific fluorescent and circular dichroism (CD) probes of AGP were determined. Dicumarol (DIC) binding was measured by CD and equilibrium dialysis.


RESULTS
DER effectively displaced probes bound to variant A, while it was less effective at displacing probes bound to variant F1/S. DER increased the binding and inverted the induced CD spectrum of DIC in the solution of variant F1/S. This phenomenon could not be brought about by the enantiomer of DER.


CONCLUSIONS
DER has high-affinity binding (K(a)> or =2x10(6) M(-1)) to variant A, while its binding to the variant F1/S is about thirty times weaker. During simultaneous binding of DER and DIC to variant F1/S a ternary complex having about four times higher affinity is formed, in which the opposite chiral conformation of DIC is favored.


CONCLUSIONS
The binding interactions found prove that AGP can simultaneously accommodate different ligand molecules. Even weakly bound ligands can provoke unexpected allosteric protein binding interactions.
Fitos
Ilona
I
Department of Molecular Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Budapest, POB 17, H-1525, Hungary. fitosi@chemres.hu
Visy
Júlia
J
Simonyi
Miklós
M
Mády
György
G
Zsila
Ferenc
F
D000494:Allosteric Regulation; D019943:Amino Acid Substitution; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D001892:Camphanes / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009961:Orosomucoid / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D013050:Spectrometry, Fluorescence
D014151:Anti-Anxiety Agents; D001892:Camphanes; D009961:Orosomucoid; D012709:Serum Albumin; C060555:deramciclane