Study of heterocycle rings binding to human serum albumin.
The binding of drugs to human serum albumin determines the drug distribution through the systemic circulation and its pharmacological effects on the organism. Then, with the aim of obtaining information concerning the drug structural features which favour their binding on seroalbumin we have studied the seroalbumin binding to the heterocyclic drugs such as warfarin, propylthiouracil and cromoglycate and to similar compounds such as 4-hydroxy-coumarin, 3-acetylcoumarin, coumarin, benzylthiouracil, propyluracil, thiouracil, chromone and chromanol. These compounds were competitively displaced by warfarin at their primary binding sites on seroalbumin. The comparative analysis of the binding data showed that heterocyclic compounds such as benzopyranes (coumarins and chromanol) and benzyl pyrimidines with 4-hydroxyl groups bind specifically in the warfarin binding site. Then, 4-hydroxyl-bencene heterocycles will displace other ligands from the subdomain IIA of the seroalbumin molecule. Therefore, we can predict that the administration concomitant of warfarin, cromoglycate, propylthiouracil and analogous heterocyclic drugs involves the displacement of the drug without 4-hydroxyl and benzyl groups, increasing their free fraction in serum and the amount of active drug.
Zatón
A M
AM
Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, Facultad de Farmacia, Vitoria-Gasteiz, Spain.
Villamor
J P
JP
D015110:4-Hydroxycoumarins / Q000378:metabolism; D001578:Benzopyrans / Q000378:metabolism*; D001667:Binding, Competitive; D002839:Chromans / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D011743:Pyrimidines / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013889:Thiouracil / Q000031:analogs & derivatives / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism
D015110:4-Hydroxycoumarins; D001578:Benzopyrans; D002839:Chromans; D011743:Pyrimidines; D012709:Serum Albumin; D013889:Thiouracil; D014859:Warfarin; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; C019269:benzylthiouracil; C068805:4-hydroxycoumarin