György Mády

Hungarian Academy of Sciences, Budapest, Budapest fovaros, Hungary

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Publications (14)30.78 Total impact

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    ABSTRACT: Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.
    International journal of biological macromolecules 11/2011; 50(3):788-95. · 2.37 Impact Factor
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    ABSTRACT: A comparative preliminary pharmacokinetic study of two buspirone preparations, Buspar and Spitomin, was performed after a single 10-mg oral dose as a pilot study in beagle dogs. The buspirone levels of blood sample series taken at 13 different times were determined by gas chromatography-mass spectrometry.For the bioanalytical analysis a new type of tetradeuterated buspirone was synthesized as an internal standard. The pharmacokinetic analysis of the concentration-time curves was carried out by the two-compartment open model.Good agreement of the all pharmacokinetic parameters obtained strongly suggests the pharmacokinetic equivalence of the two preparations.
    Pharmacy and Pharmacology Communications. 03/2011; 3(4):193 - 196.
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    ABSTRACT: Deramciclane is a novel structure among anxiolytic agents. Pharmacokinetic studies in different species indicated the possibility of strong protein binding. The binding of deramciclane to plasma from man, dog, rabbit, mouse and rat was investigated by equilibrium dialysis.Binding isotherms for human and dog plasma exhibited both saturable and non-saturable components, while binding to rabbit, rat and mouse plasmas appeared to be non-saturable. The differences could be attributed to the different α1-acid glycoprotein (AAG) affinities. The strong binding of deramciclane in human plasma (nK = 1.6 times 106 M−1) could be referred to the AAG component, and could be inhibited by several ligands known to associate with this protein. The high affinity and saturable binding of deramciclane to an acute phase component of the human plasma (AAG) necessitates careful dosage during therapeutic application.
    Pharmacy and Pharmacology Communications. 03/2011; 2(7):315 - 318.
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    ABSTRACT: 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. 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. 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. 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. The binding interactions found prove that AGP can simultaneously accommodate different ligand molecules. Even weakly bound ligands can provoke unexpected allosteric protein binding interactions.
    Biochimica et Biophysica Acta 08/2009; 1800(3):367-72. · 4.66 Impact Factor
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    Ferenc Zsila, György Mády
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    ABSTRACT: alpha(1)-Acid glycoprotein (AAG), an acute phase component of the human serum, is a prominent member of the lipocalin family of proteins showing inflammatory/immunomodulatory activities and promiscuous drug binding properties. Both three-dimensional structure of AAG and its precise biological function are still unknown and only a few endogenous AAG ligands have been described to date. CD spectroscopic studies performed with commercial AAG and the separated genetic variants revealed high-affinity binding of biliverdin (BV) and biliverdin dimethyl ester to the 'F1/S' fraction of the protein. The preferential accommodation of the right-handed, P-helicity conformers of the pigments by the protein matrix resulted in strong induced CD activity, which was utilized for estimation of the binding parameters and to locate the binding site. It was concluded that both pigments are bound in the central beta-barrel cavity of AAG, held principally by hydrophobic interactions. Possible biological implications of the BV binding ability of AAG with special emphasis on the heme oxygenase-1 pathway are discussed.
    Biochemical and Biophysical Research Communications 09/2008; 372(3):503-7. · 2.41 Impact Factor
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    ABSTRACT: Human plasma protein binding of six antimalarial agents of quinoline and acridine types was investigated by using spectroscopic techniques, affinity chromatography, ultrafiltration and HPLC methods. Induced circular dichroism (ICD) spectra showed binding of amodiaquine (AMQ), primaquine (PRQ), tafenoquine (TFQ), and quinacrine (QR) to alpha(1)-acid glycoprotein (AAG), the serum level of which greatly increases in Plasmodium infections. Association constant (K(a)) values of about 10(5)-10(6) M(-1) could be determined. Analysis of the ICD and UV spectra of the drug-AAG complexes suggested the inclusion of the ligands into the central hydrophobic cavity of the protein. Using the purified forms of the two main genetic variants of AAG, ICD data indicated the selective binding of AMQ and PRQ to the 'F1/S', while QR to the 'A' variant. Results of fluorescence experiments supported the AAG binding of these drugs and provided further insights into the binding details of TFQ and QR. Fluorescence and CD displacement experiments showed the high-affinity AAG binding of mefloquine (K(a) approximately 10(6) M(-1)). For this drug, inverse binding stereoselectivities were found with the 'F1/S' and 'A' genetic variants of AAG. HSA association constants estimated from affinity chromatography results lag behind (10(3)-10(5) M(-1)) the similar values derived for AAG. In case of chloroquine, no significant binding interaction was found either with AAG or HSA. Pharmacological aspects of the results are discussed.
    Bioorganic & medicinal chemistry 05/2008; 16(7):3759-72. · 2.82 Impact Factor
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    ABSTRACT: Human alpha(1)-acid glycoprotein (AAG) is an acute phase component of the plasma, binding numerous drugs and natural compounds with high-affinity. Using circular dichroism (CD) spectroscopy, strong AAG binding of organogold complexes was found, the molecular size and chemical structure of which differ from known AAG binding agents. The 16-membered Au(2)P(4)C(8)O(2) macrocycles interconvert rapidly between two helical forms and produce enantiomeric conformations which are in dynamic equilibrium in solution. AAG binds preferentially one of the chiral conformers as indicated by strong Cotton effects generated by intramolecular exciton coupling between the pairs of hetercyclic chromophores. Lipophilic nature of the guest molecules suggests the dominant contribution of hydrophobic interactions in the AAG binding. Comparison of the main genetic variants of AAG revealed that both the 'F1/S' and 'A' variants bind with high-affinity the gold(I) macrocycles (K(a) approximately 10(6) M(-1)). CD/fluorescence displacement, and fluorescence quenching experiments indicated inclusion of the compounds into the central beta-barrel cavity of AAG of which exact tertiary structure is yet unknown. Molecular dimensions of the gold(I) macrocycles (13 x 14 x 14 A) indicate that the principal ligand binding cavity of both the 'F1/S' and 'A' variants must be larger compared to the models published to date. Based on these findings, a novel homology model of AAG 'F1' variant was constructed using the human neutrophil gelatinase-associated lipocalin as a template. The organogold complexes were successfully docked into the central cavity of this model.
    Biochimica et Biophysica Acta 01/2008; 1784(7-8):1106-14. · 4.66 Impact Factor
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    ABSTRACT: Diazepam, a 1,4-benzodiazepine lacking chiral centre, exists in an equimolar mixture of two chiral conformers. Induced circular dichroism spectra for the binding of diazepam and its 3,3-dimethyl substituted analogues to alpha1-acid glycoprotein (AGP) revealed that opposite to human serum albumin, AGP preferably binds the P-conformers. Accordingly, slightly favoured binding of (R)-enantiomers of 3-alkyl derivatives having P-conformation was found. In case of 3-acyloxy derivatives, however, AGP preferably binds the (S)-enantiomers. Studies with the separated genetic variants of AGP proved similar binding affinities, but markedly different conformation selectivities. For diazepam bound by the F1-S variant, a P/M selectivity of about 2 could be estimated.
    Bioorganic & Medicinal Chemistry 08/2007; 15(14):4857-62. · 2.90 Impact Factor
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    ABSTRACT: Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to alpha1-acid glycoprotein (AGP) component was found to inhibit the pharmacological activity. AGP shows genetic polymorphism and the two main genetic variants have different drug binding properties. The binding characteristics of imatinib to AGP genetic variants and the possibility of its binding interactions were investigated by various methods. The results proved that binding of imatinib to the two main genetic variants is very different, the high affinity binding belongs dominantly to the F1-S variant. This interaction is accompanied with specific spectral changes (induced circular dichroism, UV change, intrinsic fluorescence quenching), suggesting that the bound ligand has chiral conformation that would largely overlap with other ligands inside the protein cavity. Binding parameters of Ka=1.7(+/-0.2)x10(6)M(-1) and n=0.94 could be determined for the binding on the F1-S variant at 37 degrees . Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa approximately 3 x 10(4)M(-1)) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.
    Biochimica et Biophysica Acta 12/2006; 1760(11):1704-12. · 4.66 Impact Factor
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    ABSTRACT: Human alpha1-acid glycoprotein displays genetic polymorphism. Different drug binding properties of the two main genetic products (F1-S and A variants) have been demonstrated. In search for specific circular dichroism (CD) probes, dicumarol and acridine orange were found to specifically bind to the F1-S and A variants, respectively. Dicumarol binding to the F1-S variant produced induced Cotton effects originating from the favored chiral conformation of the bound label. Acridine orange gave induced biphasic Cotton effects due to chiral intermolecular exciton interaction between label molecules bound to the A variant. Displacement of the CD probes by specific marker ligands was demonstrated. The induced CD spectrum of dicumarol was found to change sign in the presence of imipramine, as a manifestation of high-affinity ternary complex formation on the F1-S variant.
    Biochemical Pharmacology 03/2004; 67(4):679-88. · 4.58 Impact Factor
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    ABSTRACT: Human α1-acid glycoprotein displays genetic polymorphism. Different drug binding properties of the two main genetic products (F1-S and A variants) have been demonstrated. In search for specific circular dichroism (CD) probes, dicumarol and acridine orange were found to specifically bind to the F1-S and A variants, respectively. Dicumarol binding to the F1-S variant produced induced Cotton effects originating from the favored chiral conformation of the bound label. Acridine orange gave induced biphasic Cotton effects due to chiral intermolecular exciton interaction between label molecules bound to the A variant. Displacement of the CD probes by specific marker ligands was demonstrated. The induced CD spectrum of dicumarol was found to change sign in the presence of imipramine, as a manifestation of high-affinity ternary complex formation on the F1-S variant.
    Biochemical Pharmacology - BIOCHEM PHARMACOL. 01/2004; 67(4):679-688.
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    ABSTRACT: The binding of bimoclomol enantiomers to human plasma, its components, as well as to plasma from monkey, dog, rat, and mouse was investigated by ultrafiltration and equilibrium dialysis. The considerably stronger binding of the (-)-(S)-enantiomer found in human plasma is due to the alpha(1)-acid glycoprotein (AAG) component. The binding parameters for AAG (n(R)K(R) = 1.3 x 10(4) M(-1) and n(S)K(S) = 1.0 x 10(5) M(-1)) revealed high enantioselectivity, while the binding to human serum albumin was found to be weak (nK = 5 x 10(3) M(-1)) and not stereoselective. (-)-(S)-Bimoclomol was extensively displaced in the presence of specific marker ligands for the "FIS" subfraction of human AAG. Comparative binding studies indicated considerable differences between plasma of the five species investigated.
    Chirality 09/2002; 14(8):638-42. · 1.72 Impact Factor
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    ABSTRACT: Carotenoids form structured self-assembly upon aqueous dilution of their organic solutions. In order to test the proposal predicting carotenoid aggregates to be organized in closely packed H-type (card-pack) manner by intermolecular hydrogen bonds, the trihydroxy derivative of capsanthin (1), (6'R)-capsanthol (2) ((all-E,3R,3'S,5'R,6'R)-beta,kappa-carotene-3,3',6'-triol) was acetylated to obtain all varieties of mono-, di- and triacetates and the corresponding supramolecules were studied by UV/Vis- and CD spectroscopy. It was verified that derivatives lacking hydroxyl functions at either of the end-groups form the loosely organized J-type (head-to-tail) aggregates. A model for the structure of the J-type self-assembly is proposed. Evidence was also obtained suggesting that close contacts of carotenoid molecules are not confined to hydrogen bonding.
    Enantiomer A Journal of Stereochemistry 01/2002; 7(2-3):67-76.
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    ABSTRACT: The plasma protein interaction of a slowly eliminated substance which could be detected even after three weeks (about 0.2% of dose) in the plasma of Beagle dogs after a single oral administration of 10 mg kg−1 radiolabeled deramciclane, was determined.The substance, which could not be removed by extraction or displacement, was a metabolite irreversibly bound to serum albumin. The covalent adduct formed during the first 24 h after treatment, reached a maximum concentration between 1 and 4 days, and had an elimination half-life of approximately 10 days. The metabolite was isolated and subjected to mass spectrometry, and identified as a deramciclane derivative having a carboxylate group on the camphor ring.
    Pharmacy and Pharmacology Communications. 12/1998; 4(12).