Molecular basis of sulindac competition with specific markers for the major binding sites on human serum albumin.
This study deals with the competitive interactions of sulindac (CAS 38194-50-2) with specific markers for the major binding areas on human serum albumin (HSA): phenylbutazone (CAS 50-33-9) and warfarin (CAS 129-06-6) for Site I, and diazepam (CAS 439-14-5) for Site II. The method used is high-performance liquid affinity chromatography with HSA-immobilized stationary phase. The affinity constants during the cobinding are determined, and the major thermodynamic parameters are calculated. Based on that the nature of the intermolecular interactions involved in the binding process is hypothesized. The cobinding of sulindac and phenylbutazone is simple competitive and is dominated by hydrogen bonds. The binding affinity of sulindac is significantly decreased by R-warfarin (anticooperative binding), and conformational changes resulting in alteration of the binding mechanisms (electrostatic as well as hydrophobic interactions) are supposed. S-Warfarin hardly affects the binding affinity of sulindac. Sulindac competes with diazepam for two types of binding site: high affinity Site II where the cobinding seems to be dominated by hydrophobic bonding, and low affinity Site I, the latter affinity being significantly decreased (anticooperative binding). These results contribute to a better understanding of the molecular mechanisms of the binding of the investigated drugs with HSA.
Russeva
Veska N
VN
Department of Chemistry, Faculty of Pharmacy, Medical University, Sofia, Bulgaria.
Zhivkova
Zvetanka D
ZD
D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects*; D015415:Biomarkers; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D010653:Phenylbutazone / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D013467:Sulindac / Q000737:chemistry* / Q000378:metabolism*; D013696:Temperature; D013816:Thermodynamics; D014859:Warfarin / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D012709:Serum Albumin; D013467:Sulindac; D014859:Warfarin; D010653:Phenylbutazone; D003975:Diazepam