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1.
J Biochem Biophys Methods ; 48(1): 33-41, 2001 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-11282400

RESUMO

The binding of warfarin to human serum albumin was studied by equilibrium dialysis at pH 7.4 in a 67 mM sodium phosphate buffer at 37 degrees C. The equilibrium data were analysed using a computer program for curve fitting. The analysis was made fitting the data to equations for one, two and three classes of binding sites with one, two and three sites at the primary binding site (n(1)=1, 2 or 3). The data fitting was acceptable for two and three classes of binding sites but the best fit was obtained with the equation for two classes of binding sites, allowing us to define the binding by a model with two independent classes of binding sites on the serum albumin molecule.


Assuntos
Anticoagulantes/metabolismo , Albumina Sérica/metabolismo , Varfarina/metabolismo , Sítios de Ligação , Diálise , Humanos , Modelos Químicos , Software
2.
Chem Biol Interact ; 124(1): 1-11, 2000 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-10658898

RESUMO

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.


Assuntos
Benzopiranos/metabolismo , Pirimidinas/metabolismo , Albumina Sérica/metabolismo , 4-Hidroxicumarinas/metabolismo , Ligação Competitiva , Cromanos/metabolismo , Humanos , Cinética , Ligação Proteica , Relação Estrutura-Atividade , Tiouracila/análogos & derivados , Tiouracila/metabolismo , Varfarina/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-9675912

RESUMO

The binding of several benzopiranone derivatives to human serum albumin was determined. The antiallergic drug disodium cromoglycate binds weakly to serum albumin. However, its precursors, chromones of smaller size, were able to bind in a hydrophobic pocket in the protein, and are carried by serum albumin in blood.


Assuntos
Cromolina Sódica/química , Albumina Sérica/química , Antiasmáticos/química , Antiasmáticos/metabolismo , Cromolina Sódica/metabolismo , Humanos , Ligação Proteica , Albumina Sérica/metabolismo
4.
J Protein Chem ; 17(2): 115-9, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9535273

RESUMO

The binding of several benzopyranes to serum albumin was studied by equilibrium dialysis at pH 7.4 in a 67 mM sodium phosphate buffer at 37 degrees C. The equilibrium data were analyzed using a computer program for curve fitting. The binding isotherm for warfarin, 4-hydroxycoumarin, 4-chromanol, coumarin, 3-acetylcoumarin, and benzoic acid can be described by two stoichiometric dissociation constants. Elimination of the 4-hydroxyl group in the coumarin chemical structures decreases the binding affinity of the compounds on the primary binding site of serum albumin, with 4-chromanol the smallest ligand which binds to seroalbumin with high affinity. Thus, the affinity of 4-benzopyranol and the 4-hydroxybenzopyranones greater than that of benzopyranones. On the other hand, elimination of the 2-oxo group in the benzopyranone chemical structures decreases affinity for the secondary binding site.


Assuntos
Cromanos/metabolismo , Cumarínicos/metabolismo , Albumina Sérica/metabolismo , Varfarina/metabolismo , Sítios de Ligação , Humanos , Ligação Proteica , Albumina Sérica/química , Relação Estrutura-Atividade
5.
Biophys Chem ; 69(2-3): 233-7, 1997 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-9474756

RESUMO

As the spectra and binding parameters calculated for the thiouracil-albumin interaction change with the protein concentration, a human seroalbumin conformational change depending on protein concentration has been suggested. This protein-conformational change is tested by dilatometry and viscosimetry. At low concentrations, albumin showed a greater thiouracil binding capacity and a second positive peak in its interaction with the drug, detected by difference spectroscopy. Both effects are due to a monomerisation of protein dimers and not to a conformational change depending on protein concentration. This monomerisation would imply a major accessibility of thiouracil and propylthiouracil to other binding sites on HSA.


Assuntos
Conformação Proteica , Albumina Sérica/metabolismo , Tiouracila/metabolismo , Sítios de Ligação , Dimerização , Humanos , Ligação Proteica , Espectrofotometria , Raios Ultravioleta , Viscosidade
6.
J Enzyme Inhib ; 10(2): 135-9, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8835938

RESUMO

The antiallergic drug disodium cromoglycate and its non-antiallergic analogue dicoumarol, inhibit the enzymatic activity of phosphodiesterase with KI values of 0.8.10(-9) M and 1.6.10(-9) M, respectively. It seems that the dichromone group is responsible for this inhibition, independently of its antiallergic effect.


Assuntos
Cromolina Sódica/farmacologia , Inibidores de Fosfodiesterase/farmacologia , 5'-Nucleotidase/metabolismo , Animais , Antiasmáticos/farmacologia , Bovinos , AMP Cíclico/metabolismo , Dicumarol/análogos & derivados , Dicumarol/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cinética , Camundongos , Estrutura Molecular , Miocárdio/enzimologia , Venenos de Serpentes/enzimologia
7.
FEBS Lett ; 374(2): 192-4, 1995 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-7589532

RESUMO

In this paper, the activity of horseradish peroxidase was further determined in the presence of several uracil derivatives. The rate of guaiacol peroxidation decreases in presence of 2-thiouracil and of 6-n-propyl-2-thiouracil, but is not changed by 6-n-propyluracil nor uracil. Thus, thiouracils inhibit horseradish peroxidase in a noncompetitive form. The binding of 6-n-propyl-2-thiouracil, 2-thiouracil, 6-n-propyluracil and uracil with horseradish peroxidase shows difference spectra due to changes in the environment of heme group in peroxidase. Then, the binding sites for these uracil derivatives are in an hydrophobic pocket at the heme periphery of peroxidase. The lesser binding rates were for uracil and propyluracil, which did not inhibit the peroxidase activity. These results point to the thiol group in uracils as responsible for the inhibition of peroxidase activity through interaction with an allosteric binding site, in peroxidase heme environment.


Assuntos
Antitireóideos/farmacologia , Peroxidase do Rábano Silvestre/antagonistas & inibidores , Tiouracila/farmacologia , Peroxidase do Rábano Silvestre/metabolismo , Ligação Proteica , Espectrofotometria Ultravioleta , Tiouracila/química , Uracila/análogos & derivados , Uracila/farmacologia
8.
Chem Biol Interact ; 97(2): 169-74, 1995 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-7606814

RESUMO

It is known that binding site I on human serum albumin (HSA) consists of a zone of two overlapping regions: the specific binding region represented by warfarin binding and the specific binding region represented by azapropazone and phenylbutazone binding. In this paper binding parameters to defatted HSA and to HSA with fatty acids (molar ratio of fatty acid/HSA = 4) were compared. High-affinity binding sites for warfarin, 4-chromanol, 4-hydroxycoumarin, coumarin, 3-acetylcoumarin and phenylbutazone (759,549 M-1 > Ka > 67,024 M-1) constitute binding site I on HSA. In this binding area defatted HSA can bind two molecules of warfarin, but the presence of fatty acids diminish the binding capacity of warfarin to HSA (2 > n > 1).


Assuntos
Cumarínicos/metabolismo , Ácidos Graxos/metabolismo , Receptores de Albumina/metabolismo , Albumina Sérica/metabolismo , Transporte Biológico/fisiologia , Cromanos/metabolismo , Humanos , Ligantes , Fenilbutazona/metabolismo , Varfarina/metabolismo
9.
J Enzyme Inhib ; 8(2): 87-95, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7539075

RESUMO

Disodium cromoglycate (DSCG) inhibits alkaline phosphatase in a non-competitive manner, the enzyme undergoing a conformational change which is attenuated by the presence of calcium ions. The structurally related pyranone and benzoic acid are weak inhibitors of the enzyme and produce a similar conformational change. Coumarin does not induce any conformational change in the enzyme suggesting that the 4-oxo group in DSCG may be essential for its effect.


Assuntos
Fosfatase Alcalina/antagonistas & inibidores , Cromolina Sódica/análogos & derivados , Cromolina Sódica/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Benzoatos/farmacologia , Ácido Benzoico , Cálcio/metabolismo , Bovinos , Galinhas , Cumarínicos/farmacologia , Cromolina Sódica/química , Dicumarol/farmacologia , Cinética , Conformação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Viscosidade
10.
J Biochem Biophys Methods ; 27(2): 87-94, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8227947

RESUMO

Propylthiouracil is an antithyroid drug which is carried by the blood, thanks to its binding with human seroalbumin (HSA), and induces a structural alteration in HSA that changes the binding capability of other ligands. Then, with the aim of fixing the functional group in propylthiouracil involved in the interactions with HSA, the binding parameters for several uracil derivatives bound on HSA have been estimated. Interaction of propyluracil, thiouracil and propylthiouracil with HSA leads to the formation of complexes that show spectral shifts. These spectral shifts are a measure of the fraction of chromophoric groups, which is perturbed in the interaction with HSA, and thus can be used in the ligand binding estimate. The difference spectroscopy results correspond to the binding on a single centre in HSA. The difference spectra of propyluracils in seroalbumin coincide with those of propyluracils in a perturbant solvent (ethanol). On the other hand, propylthiouracil and propyluracil bind to seroalbumin on a larger scale than uracil and thiouracil. Thus, we can conclude that this binding is strengthened by hydrophobic interactions between the propyl group in propyluracils and apolar substituents on HSA.


Assuntos
Propiltiouracila/metabolismo , Albumina Sérica/metabolismo , Humanos , Ligação Proteica , Espectrofotometria Ultravioleta/métodos , Uracila/análogos & derivados , Uracila/metabolismo
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