Magdaléna Májeková - Academia.edu (original) (raw)
Papers by Magdaléna Májeková
Biomolecules
Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in c... more Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in cells by pumping calcium ions from the cytoplasm to the lumen while undergoing substantial conformational changes, which can be stabilized or prevented by various compounds. Here we attempted to clarify the molecular mechanism of action of new inhibitor rutin arachidonate, one of the series of the acylated rutin derivatives. We performed molecular dynamics simulations of SERCA1a protein bound to rutin arachidonate positioned in a pure dipalmitoylphosphatidylcholine bilayer membrane. Our study predicted the molecular basis for the binding of rutin arachidonate towards SERCA1a in the vicinity of the binding site of calcium ions and near the location of the well-known inhibitor thapsigargin. The stable hydrogen bond between Glu771 and rutin arachidonate plays a key role in the binding. SERCA1a is kept in the E2 conformation preventing the formation of important salt bridges between the side ...
Future Medicinal Chemistry
Acidic conditions induce protonation of two important parts of the active site of the enzymatic c... more Acidic conditions induce protonation of two important parts of the active site of the enzymatic complex: His110 (which often interacts with inhibitors via H-bond) and NADP +. As the resulting effect, the cavity of the active site is becoming more positive, when compared with the surrounding protein surface and physiological pH. "
![Research paper thumbnail of [5-(Benzyloxy)-1H-indol-1-yl]acetic acid, an aldose reductase inhibitor and PPARγ ligand](https://attachments.academia-assets.com/74121309/thumbnails/1.jpg)
](Acta Biochimica Polonica, 2015
Based on overlapping structural requirements for both efficient aldose reductase inhibitors and P... more Based on overlapping structural requirements for both efficient aldose reductase inhibitors and PPAR ligands, [5-(benzyloxy)-1H-indol-1-yl]acetic acid (compound 1) was assessed for inhibition of aldose reductase and ability to interfere with PPARγ. Aldose reductase inhibition by 1 was characterized by IC 50 in submicromolar and low micromolar range, for rat and human enzyme, respectively. Selectivity in relation to the closely related rat kidney aldehyde reductase was characterized by approx. factor 50. At organ level in isolated rat lenses, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner. To identify crucial interactions within the enzyme binding site, molecular docking simulations were performed. Based on luciferase reporter assays, compound 1 was found to act as a ligand for PPARγ, yet with rather low activity. On balance, compound 1 is suggested as a promising lead-like scaffold for agents with the potential to interfere with multiple targets in diabetes.
Journal of Molecular Structure: THEOCHEM, 1991
A hierarchy of useful expressions for evaluating the Gibbs free energy of dispersion and repulsio... more A hierarchy of useful expressions for evaluating the Gibbs free energy of dispersion and repulsion interactions in condensed media has been developed. The method is based on the approximate London and Born formulae for solute-solvent interactions. Five different approximations are presented ranging from the simple molecule-molecule type formula up to more advanced atomatom type expressions which take into account a uniform solvent distribution and specific solutesolvent molecular orientations. The quality of the method and the particular approximations have been tested on a wide series of solutes of various polarities and symmetries in different solvents. The nonadditivity of intermolecular dispersion and repulsion interactions is treated using structure-dependent atomic parameters. The derived formulae are compatible with continuum models of solvation.
![Research paper thumbnail of Antioxidant action of 3-mercapto-5 H -1,2,4-triazino[5,6- b ]indole-5-acetic acid, an efficient aldose reductase inhibitor, in a 1,1′-diphenyl-2-picrylhydrazyl assay and in the cellular system of isolated erythrocytes exposed to tert -butyl hydroperoxide](https://attachments.academia-assets.com/74121301/thumbnails/1.jpg)
](Redox Report, 2015
Objectives: The subject of this study was 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid... more Objectives: The subject of this study was 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (compound 1), an efficient aldose reductase inhibitor of high selectivity. The antioxidant action of 1 was investigated in greater detail by employing a 1,1 ′-diphenyl-2-picrylhydrazyl (DPPH) test and in the system of isolated rat erythrocytes. Methods: First, the compound was subjected to the DPPH test. Second, the overall antioxidant action of the compound was studied in the cellular system of isolated rat erythrocytes oxidatively stressed by free radicals derived from the lipophilic tert-butyl hydroperoxide. The uptake kinetics of 1 was studied and osmotic fragility of the erythrocytes was evaluated. Results: The DPPH test revealed significant antiradical activity of 1. One molecule of 1 was found to quench 1.48 ± 0.06 DPPH radicals. In the system of isolated erythrocytes, the compound was readily taken up by the cells followed by their protection against free radical-initiated hemolysis. Osmotic fragility of the erythrocytes was not affected by 1. Conclusions: The results demonstrated the ability of 1 to scavenge DPPH and to protect intact erythrocytes against oxidative damage induced by peroxyl radicals. By affecting both the polyol pathway and oxidative stress, the compound represents an example of a promising agent for multi-target pharmacology of diabetic complications.
Aldo-keto reductases belong to the recently indicated targets in neurodegenerative diseases due t... more Aldo-keto reductases belong to the recently indicated targets in neurodegenerative diseases due to the revealed correlation between neurodegenerative and type 2 diabetes mellitus related changes in the brain. As aldose reductase (ALR2) is one of the most promising targets in reducing glucose toxicity, ALR2 inhibitors could represent prospective compounds in developing the multi-target drug leads. We focused on a set of 20 indole derivatives with recently determined inhibition activities towards ALR2 and known selectivity factors as compared with aldehyde reductase (ALR1). We performed a molecular modeling study on the interaction of the indole compounds with monoamine oxidase A and B. The study was based on docking calculation and subsequent full optimization of the complexes. Experimental conformation of human MAO-A and MAO-B inhibition activities of effective ALR2 inhibitors from the group of indole-1-acetic derivatives (13 and 20) is also presented. Compound 20 exhibited prospect...
Farmacia
The paper presents the results of in silico evaluations performed on a group of 127 compounds wit... more The paper presents the results of in silico evaluations performed on a group of 127 compounds with dibenzothiepine structure. The predictions were focused on molecular descriptors relevant for quantitative estimation of penetration across various biological barriers. The results indicated a low solubility together with high permeability profile, with considerable impact of gastro-intestinal, endogenous tensioactives. The predicted pharmacokinetic characteristics are favorable for expressing a potential psychotropic activity.
Journal of Molecular Structure: THEOCHEM, 1988
An extended version of the polarixable continuum model of solvation is presented. Principles of t... more An extended version of the polarixable continuum model of solvation is presented. Principles of the particular models for electrostatic, dispersion, repulsion, and cavitation terms evaluation are shown and the recent state in methodology is described. Modifications suitable for large biomolecules, fields of application and possible further development are discussed. An illustrative example showing the significance of individual solvation Gibbs free energy contributions is given.
Journal of Molecular Structure: THEOCHEM, 1989
A modification of the polarixable continuum model (PCM) of solvation applicable within semiempiri... more A modification of the polarixable continuum model (PCM) of solvation applicable within semiempirical SCF calculations has been developed. Main principles and comparison to its original ab initio version are discussed. Further, a new approximation, the representative point charge (RPC) method, useful for handling solvation of large biomolecules within continuum models of solvation has been derived. The basic methodology, as well as its comparison to the original PCM model on both the ab initio and the semiempirical levels, is given. An illustrative example of solvation of nucleic acid bases is presented.
Bratislavské lekárske listy, 2005
Activated blood platelets play a key role in the genesis of many pathological states. Several stu... more Activated blood platelets play a key role in the genesis of many pathological states. Several studies have documented that beta-blockers can influence platelet aggregation. Carvedilol, a third generation non-selective agent with vasodilatory properties, is successfully used in pathological states accompanied with platelet hyperreactivity, however information on its antiplatelet activity is lacking. The aim of this study was to analyse the in vitro effect of carvedilol on aggregation of human blood platelets, to compare this effect with the effect of propranolol and atenolol, and to determine whether its suggested antiaggregatory effect was accompanied with reduced thromboxane B2 formation. Moreover, some physico-chemical parameters of the drugs tested were calculated and compared. Platelets were isolated by differential centrifugation and platelet aggregation was measured by the turbidimetric method. The amount of thromboxane B2 was measured by the radioimmunoassay method. Physico-c...
General physiology and biophysics, 1998
The binding site of a PCB-degrading enzyme was mapped using the published data on biodegradation ... more The binding site of a PCB-degrading enzyme was mapped using the published data on biodegradation rates of individual PCB congeners by the Acinetobacter P6 strain. For this purpose an approach allowing for multiple binding modes of individual congeners, resulting from the symmetry of the biphenyl skeleton, was used. The effect of substitution patterns and conformational flexibility of individual congeners on their binding to a protein were investigated. The resulting map of the binding site is described by three parameters that indicate the importance of positions 4, 5', 5, 2' in a basic substitution pattern, the first two being favourable while the other two unfavourable for binding. An incorporation of conformational energy dependences of individual ligands into the model showed that ligand's conformation is either not a limiting factor for binding or that ligands bind in their relaxed conformations.
Methods in Molecular Biology, 2014
Great effort has been devoted to design and synthesize biologically active and pharmacologically ... more Great effort has been devoted to design and synthesize biologically active and pharmacologically acceptable antioxidants. Although a number of efficient antioxidant compounds have been designed, synthesized, and tested in animals, none of them have demonstrated sufficient efficacy in human clinical trials without undesirable side effects. Thus new pharmacologically applicable antioxidants have been sought for. Substituted pyridoindoles represent a broad spectrum of pharmacologically active substances including highly effective scavengers of reactive oxygen species. The hexahydropyridoindole scaffold represents a valuable lead with a great deal of knowledge on molecular mechanisms of free radical scavenging, on bioavailability and toxicity. Its modification may yield congeners tailored according to specific requirements for antiradical efficacy, lipophilicity, and basicity, meeting the aim of providing a pharmacologically practicable antioxidant drug as exemplified by the novel derivative SMe1EC2.
General physiology and biophysics, 2012
Although multiple biochemical pathways are likely to be responsible for the pathogenesis of diabe... more Although multiple biochemical pathways are likely to be responsible for the pathogenesis of diabetic complications, substantial evidence suggests a key role for the polyol pathway and oxidative stress initiated by hyperglycemia. Thus aldose reductase, the first enzyme of the polyol pathway, has been identified as a potential target of pharmacological intervention to prevent diabetic complications. Aldose reductase inhibitors endowed with antioxidant activity would be dually beneficial. The aim of the study was to evaluate the structure-activity relationship of commercially available indole derivatives supported by the molecular modeling of their interaction with the enzyme aldose reductase from the viewpoint of the inhibitory effect on the enzyme and their antioxidant activity. The partially purified aldose reductase was prepared from rabbit eye lenses. In vitro inhibiton of the aldose reductase was determined by a conventional method. Antioxidant action of the compounds was documented in a DPPH test. Marked differences were recorded in the aldose reductase inhibition activities of 1-and 3-indole acetic acid derivatives. The interaction energies of the inhibitor vs. enzyme-NADP + complexes, calculated by computer aided molecular modeling, were in agreement with the higher inhibitory efficacy of 1-indole acetic acid in contrast with 3-indole acetic acid. The more efficient 1-indole acetic acid was proved to create stronger electrostatic interaction with NADP +. However, the order of the antioxidant activities of the compounds studied was not in agreement with that of the inhibitory efficacies.
Journal of Medicinal Chemistry, 2015
Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected fro... more Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations.
General physiology and biophysics, 2015
Many natural and synthetic quinones and naphthoquinones possess a variety of beneficial pharmacol... more Many natural and synthetic quinones and naphthoquinones possess a variety of beneficial pharmacological properties. In plants, the cytotoxic properties of quinones serve in their defensive roles against invading bacteria, fungi and parasites. In this regard many quinones as well as polyphenols, exerting generally toxicity at high dosages, are able to induce favorable hormetic responses at a low dosage. The novel chloronaphthoquinone derivative of quercetin (CHNQ) showed a profound cytotoxicity followed by enhancement of intracellular generation of oxidants in human neonatal B-HNF-3 fibroblasts. Its synthetic precursors, quercetin and 2-chloro-3-hydroxy-[1,4]naphthoquinone, failed to induce these effects, and paradoxically, only CHNQ at a low concetration provided partial protection of the cells against oxidative challenge. Thus, the novel quinonoid-polyphenol CHNQ might have a merit in the search for new prospective agents in prevention and management of ageing and ageing-related pathologies.
Redox Report, 2006
To address the question why isoluminol, but not luminol, failed to detect oxidants produced intra... more To address the question why isoluminol, but not luminol, failed to detect oxidants produced intracellularly, differences between these luminophores were investigated with respect to physicochemical parameters and the character of chemiluminescence signal. Our results showed the isoluminol molecule to be more polar, more hydrophilic and possessing lower ability to form intramolecular bonds than the luminol molecule. Therefore, isoluminol: (i) only slightly pervaded biological membranes; (ii) depended essentially on extracellular peroxidase; (iii) did not produce chemiluminescence in the presence of extracellular scavengers; and (iv) it could be considered a specific detector of extracellular radicals. On the other hand, the physicochemical parameters of luminol and partial resistance of its chemiluminescence to the effect of extracellular inhibitors proved the lipo/hydrophilic character of this luminophore and thus its ability to interact with radicals both outside and inside of cells. The luminol chemiluminescence measured in the presence of extracellular scavengers and the isoluminol chemiluminescence were used with the intention to differentiate the effects of two antihistamine drugs on intra-and extracellular radical formation. In activated human neutrophils, brompheniramine inhibited the extracellular and potentiated the intracellular part of chemiluminescence signal, whereas a reducing effect of loratadine was observed in both compartments.
Molecular and Cellular Biochemistry, 2014
In this study we analyzed the protective action of the flavonoid rutin on peroxynitrite (ONOO(-))... more In this study we analyzed the protective action of the flavonoid rutin on peroxynitrite (ONOO(-)) mediated impairment of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1 isoform), especially related to posttranslational and conformational changes. Rutin concentration dependently protected ONOO(-) induced SERCA1 activity decrease with effective concentration EC50 of 18 ± 1.5 µM. Upon treatment with ONOO(-), this flavonoid also prevented SERCA1 from thiol group oxidation and significantly reduced tyrosine nitration and protein carbonyl formation. In the absence of ONOO(-), rutin (250 and 350 µM) stimulated SERCA1 activity at 2.1 mM [ATP] and 10 µM [Ca(2+)]free. According to changes in the kinetic parameters V max and K m with regard to [ATP], rutin (250 µM) increased the rate of enzyme catalysis and decreased the affinity of SERCA1 to ATP. FITC fluorescence decreased in the presence of rutin (150 and 250 µM), indicating conformational changes in the cytosolic ATP binding region of SERCA1. In silico study confirmed the binding of rutin in the cytosolic region of SERCA1, in the vicinity of the ATP binding site. Residue Glu183 localized within the conserved TGES loop was identified to play a key role in rutin-SERCA1 interaction (H-bond length of 1.7 Å), elucidating the ability of rutin to affect the affinity of SERCA1 to ATP. The binding of rutin in the proximity of Lys515 is likely to cause a decrease in FITC fluorescence.
Central European Journal of Medicine, 2006
α1 — adrenolytic activities of pyridoindole derivatives recently synthesized in the Institute of ... more α1 — adrenolytic activities of pyridoindole derivatives recently synthesized in the Institute of Experimental Pharmacology, Slovak Academy of Sciences, were measured. A characteristic set of derivatives (five active, one with a threshold activity and two inactive) was chosen and an elementary structure-activity study was performed. The structure and energy properties were estimated by quantum-chemical semiempirical AM1 and molecular mechanics methods. The ionization constants pKα of the individual derivatives were calculated by program Pallas or estimated by potenciometric titration. The α 1 blocking activities were measured by rat thoracic aorta model. The experimental model used was not α 1 — adrenoreceptor subtypes specific, however, the α 1D subtype could be considered to be a predominant type in a rat aorta. The obtained physico-chemical parameters were then compared with the blocking activities of the derivatives and following determining characters for α 1 — adrenolytic activ...
Biomolecules
Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in c... more Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) maintains the level of calcium concentration in cells by pumping calcium ions from the cytoplasm to the lumen while undergoing substantial conformational changes, which can be stabilized or prevented by various compounds. Here we attempted to clarify the molecular mechanism of action of new inhibitor rutin arachidonate, one of the series of the acylated rutin derivatives. We performed molecular dynamics simulations of SERCA1a protein bound to rutin arachidonate positioned in a pure dipalmitoylphosphatidylcholine bilayer membrane. Our study predicted the molecular basis for the binding of rutin arachidonate towards SERCA1a in the vicinity of the binding site of calcium ions and near the location of the well-known inhibitor thapsigargin. The stable hydrogen bond between Glu771 and rutin arachidonate plays a key role in the binding. SERCA1a is kept in the E2 conformation preventing the formation of important salt bridges between the side ...
Future Medicinal Chemistry
Acidic conditions induce protonation of two important parts of the active site of the enzymatic c... more Acidic conditions induce protonation of two important parts of the active site of the enzymatic complex: His110 (which often interacts with inhibitors via H-bond) and NADP +. As the resulting effect, the cavity of the active site is becoming more positive, when compared with the surrounding protein surface and physiological pH. "
Acta Biochimica Polonica, 2015
Based on overlapping structural requirements for both efficient aldose reductase inhibitors and P... more Based on overlapping structural requirements for both efficient aldose reductase inhibitors and PPAR ligands, [5-(benzyloxy)-1H-indol-1-yl]acetic acid (compound 1) was assessed for inhibition of aldose reductase and ability to interfere with PPARγ. Aldose reductase inhibition by 1 was characterized by IC 50 in submicromolar and low micromolar range, for rat and human enzyme, respectively. Selectivity in relation to the closely related rat kidney aldehyde reductase was characterized by approx. factor 50. At organ level in isolated rat lenses, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner. To identify crucial interactions within the enzyme binding site, molecular docking simulations were performed. Based on luciferase reporter assays, compound 1 was found to act as a ligand for PPARγ, yet with rather low activity. On balance, compound 1 is suggested as a promising lead-like scaffold for agents with the potential to interfere with multiple targets in diabetes.
Journal of Molecular Structure: THEOCHEM, 1991
A hierarchy of useful expressions for evaluating the Gibbs free energy of dispersion and repulsio... more A hierarchy of useful expressions for evaluating the Gibbs free energy of dispersion and repulsion interactions in condensed media has been developed. The method is based on the approximate London and Born formulae for solute-solvent interactions. Five different approximations are presented ranging from the simple molecule-molecule type formula up to more advanced atomatom type expressions which take into account a uniform solvent distribution and specific solutesolvent molecular orientations. The quality of the method and the particular approximations have been tested on a wide series of solutes of various polarities and symmetries in different solvents. The nonadditivity of intermolecular dispersion and repulsion interactions is treated using structure-dependent atomic parameters. The derived formulae are compatible with continuum models of solvation.
Redox Report, 2015
Objectives: The subject of this study was 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid... more Objectives: The subject of this study was 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (compound 1), an efficient aldose reductase inhibitor of high selectivity. The antioxidant action of 1 was investigated in greater detail by employing a 1,1 ′-diphenyl-2-picrylhydrazyl (DPPH) test and in the system of isolated rat erythrocytes. Methods: First, the compound was subjected to the DPPH test. Second, the overall antioxidant action of the compound was studied in the cellular system of isolated rat erythrocytes oxidatively stressed by free radicals derived from the lipophilic tert-butyl hydroperoxide. The uptake kinetics of 1 was studied and osmotic fragility of the erythrocytes was evaluated. Results: The DPPH test revealed significant antiradical activity of 1. One molecule of 1 was found to quench 1.48 ± 0.06 DPPH radicals. In the system of isolated erythrocytes, the compound was readily taken up by the cells followed by their protection against free radical-initiated hemolysis. Osmotic fragility of the erythrocytes was not affected by 1. Conclusions: The results demonstrated the ability of 1 to scavenge DPPH and to protect intact erythrocytes against oxidative damage induced by peroxyl radicals. By affecting both the polyol pathway and oxidative stress, the compound represents an example of a promising agent for multi-target pharmacology of diabetic complications.
Aldo-keto reductases belong to the recently indicated targets in neurodegenerative diseases due t... more Aldo-keto reductases belong to the recently indicated targets in neurodegenerative diseases due to the revealed correlation between neurodegenerative and type 2 diabetes mellitus related changes in the brain. As aldose reductase (ALR2) is one of the most promising targets in reducing glucose toxicity, ALR2 inhibitors could represent prospective compounds in developing the multi-target drug leads. We focused on a set of 20 indole derivatives with recently determined inhibition activities towards ALR2 and known selectivity factors as compared with aldehyde reductase (ALR1). We performed a molecular modeling study on the interaction of the indole compounds with monoamine oxidase A and B. The study was based on docking calculation and subsequent full optimization of the complexes. Experimental conformation of human MAO-A and MAO-B inhibition activities of effective ALR2 inhibitors from the group of indole-1-acetic derivatives (13 and 20) is also presented. Compound 20 exhibited prospect...
Farmacia
The paper presents the results of in silico evaluations performed on a group of 127 compounds wit... more The paper presents the results of in silico evaluations performed on a group of 127 compounds with dibenzothiepine structure. The predictions were focused on molecular descriptors relevant for quantitative estimation of penetration across various biological barriers. The results indicated a low solubility together with high permeability profile, with considerable impact of gastro-intestinal, endogenous tensioactives. The predicted pharmacokinetic characteristics are favorable for expressing a potential psychotropic activity.
Journal of Molecular Structure: THEOCHEM, 1988
An extended version of the polarixable continuum model of solvation is presented. Principles of t... more An extended version of the polarixable continuum model of solvation is presented. Principles of the particular models for electrostatic, dispersion, repulsion, and cavitation terms evaluation are shown and the recent state in methodology is described. Modifications suitable for large biomolecules, fields of application and possible further development are discussed. An illustrative example showing the significance of individual solvation Gibbs free energy contributions is given.
Journal of Molecular Structure: THEOCHEM, 1989
A modification of the polarixable continuum model (PCM) of solvation applicable within semiempiri... more A modification of the polarixable continuum model (PCM) of solvation applicable within semiempirical SCF calculations has been developed. Main principles and comparison to its original ab initio version are discussed. Further, a new approximation, the representative point charge (RPC) method, useful for handling solvation of large biomolecules within continuum models of solvation has been derived. The basic methodology, as well as its comparison to the original PCM model on both the ab initio and the semiempirical levels, is given. An illustrative example of solvation of nucleic acid bases is presented.
Bratislavské lekárske listy, 2005
Activated blood platelets play a key role in the genesis of many pathological states. Several stu... more Activated blood platelets play a key role in the genesis of many pathological states. Several studies have documented that beta-blockers can influence platelet aggregation. Carvedilol, a third generation non-selective agent with vasodilatory properties, is successfully used in pathological states accompanied with platelet hyperreactivity, however information on its antiplatelet activity is lacking. The aim of this study was to analyse the in vitro effect of carvedilol on aggregation of human blood platelets, to compare this effect with the effect of propranolol and atenolol, and to determine whether its suggested antiaggregatory effect was accompanied with reduced thromboxane B2 formation. Moreover, some physico-chemical parameters of the drugs tested were calculated and compared. Platelets were isolated by differential centrifugation and platelet aggregation was measured by the turbidimetric method. The amount of thromboxane B2 was measured by the radioimmunoassay method. Physico-c...
General physiology and biophysics, 1998
The binding site of a PCB-degrading enzyme was mapped using the published data on biodegradation ... more The binding site of a PCB-degrading enzyme was mapped using the published data on biodegradation rates of individual PCB congeners by the Acinetobacter P6 strain. For this purpose an approach allowing for multiple binding modes of individual congeners, resulting from the symmetry of the biphenyl skeleton, was used. The effect of substitution patterns and conformational flexibility of individual congeners on their binding to a protein were investigated. The resulting map of the binding site is described by three parameters that indicate the importance of positions 4, 5', 5, 2' in a basic substitution pattern, the first two being favourable while the other two unfavourable for binding. An incorporation of conformational energy dependences of individual ligands into the model showed that ligand's conformation is either not a limiting factor for binding or that ligands bind in their relaxed conformations.
Methods in Molecular Biology, 2014
Great effort has been devoted to design and synthesize biologically active and pharmacologically ... more Great effort has been devoted to design and synthesize biologically active and pharmacologically acceptable antioxidants. Although a number of efficient antioxidant compounds have been designed, synthesized, and tested in animals, none of them have demonstrated sufficient efficacy in human clinical trials without undesirable side effects. Thus new pharmacologically applicable antioxidants have been sought for. Substituted pyridoindoles represent a broad spectrum of pharmacologically active substances including highly effective scavengers of reactive oxygen species. The hexahydropyridoindole scaffold represents a valuable lead with a great deal of knowledge on molecular mechanisms of free radical scavenging, on bioavailability and toxicity. Its modification may yield congeners tailored according to specific requirements for antiradical efficacy, lipophilicity, and basicity, meeting the aim of providing a pharmacologically practicable antioxidant drug as exemplified by the novel derivative SMe1EC2.
General physiology and biophysics, 2012
Although multiple biochemical pathways are likely to be responsible for the pathogenesis of diabe... more Although multiple biochemical pathways are likely to be responsible for the pathogenesis of diabetic complications, substantial evidence suggests a key role for the polyol pathway and oxidative stress initiated by hyperglycemia. Thus aldose reductase, the first enzyme of the polyol pathway, has been identified as a potential target of pharmacological intervention to prevent diabetic complications. Aldose reductase inhibitors endowed with antioxidant activity would be dually beneficial. The aim of the study was to evaluate the structure-activity relationship of commercially available indole derivatives supported by the molecular modeling of their interaction with the enzyme aldose reductase from the viewpoint of the inhibitory effect on the enzyme and their antioxidant activity. The partially purified aldose reductase was prepared from rabbit eye lenses. In vitro inhibiton of the aldose reductase was determined by a conventional method. Antioxidant action of the compounds was documented in a DPPH test. Marked differences were recorded in the aldose reductase inhibition activities of 1-and 3-indole acetic acid derivatives. The interaction energies of the inhibitor vs. enzyme-NADP + complexes, calculated by computer aided molecular modeling, were in agreement with the higher inhibitory efficacy of 1-indole acetic acid in contrast with 3-indole acetic acid. The more efficient 1-indole acetic acid was proved to create stronger electrostatic interaction with NADP +. However, the order of the antioxidant activities of the compounds studied was not in agreement with that of the inhibitory efficacies.
Journal of Medicinal Chemistry, 2015
Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected fro... more Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations.
General physiology and biophysics, 2015
Many natural and synthetic quinones and naphthoquinones possess a variety of beneficial pharmacol... more Many natural and synthetic quinones and naphthoquinones possess a variety of beneficial pharmacological properties. In plants, the cytotoxic properties of quinones serve in their defensive roles against invading bacteria, fungi and parasites. In this regard many quinones as well as polyphenols, exerting generally toxicity at high dosages, are able to induce favorable hormetic responses at a low dosage. The novel chloronaphthoquinone derivative of quercetin (CHNQ) showed a profound cytotoxicity followed by enhancement of intracellular generation of oxidants in human neonatal B-HNF-3 fibroblasts. Its synthetic precursors, quercetin and 2-chloro-3-hydroxy-[1,4]naphthoquinone, failed to induce these effects, and paradoxically, only CHNQ at a low concetration provided partial protection of the cells against oxidative challenge. Thus, the novel quinonoid-polyphenol CHNQ might have a merit in the search for new prospective agents in prevention and management of ageing and ageing-related pathologies.
Redox Report, 2006
To address the question why isoluminol, but not luminol, failed to detect oxidants produced intra... more To address the question why isoluminol, but not luminol, failed to detect oxidants produced intracellularly, differences between these luminophores were investigated with respect to physicochemical parameters and the character of chemiluminescence signal. Our results showed the isoluminol molecule to be more polar, more hydrophilic and possessing lower ability to form intramolecular bonds than the luminol molecule. Therefore, isoluminol: (i) only slightly pervaded biological membranes; (ii) depended essentially on extracellular peroxidase; (iii) did not produce chemiluminescence in the presence of extracellular scavengers; and (iv) it could be considered a specific detector of extracellular radicals. On the other hand, the physicochemical parameters of luminol and partial resistance of its chemiluminescence to the effect of extracellular inhibitors proved the lipo/hydrophilic character of this luminophore and thus its ability to interact with radicals both outside and inside of cells. The luminol chemiluminescence measured in the presence of extracellular scavengers and the isoluminol chemiluminescence were used with the intention to differentiate the effects of two antihistamine drugs on intra-and extracellular radical formation. In activated human neutrophils, brompheniramine inhibited the extracellular and potentiated the intracellular part of chemiluminescence signal, whereas a reducing effect of loratadine was observed in both compartments.
Molecular and Cellular Biochemistry, 2014
In this study we analyzed the protective action of the flavonoid rutin on peroxynitrite (ONOO(-))... more In this study we analyzed the protective action of the flavonoid rutin on peroxynitrite (ONOO(-)) mediated impairment of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1 isoform), especially related to posttranslational and conformational changes. Rutin concentration dependently protected ONOO(-) induced SERCA1 activity decrease with effective concentration EC50 of 18 ± 1.5 µM. Upon treatment with ONOO(-), this flavonoid also prevented SERCA1 from thiol group oxidation and significantly reduced tyrosine nitration and protein carbonyl formation. In the absence of ONOO(-), rutin (250 and 350 µM) stimulated SERCA1 activity at 2.1 mM [ATP] and 10 µM [Ca(2+)]free. According to changes in the kinetic parameters V max and K m with regard to [ATP], rutin (250 µM) increased the rate of enzyme catalysis and decreased the affinity of SERCA1 to ATP. FITC fluorescence decreased in the presence of rutin (150 and 250 µM), indicating conformational changes in the cytosolic ATP binding region of SERCA1. In silico study confirmed the binding of rutin in the cytosolic region of SERCA1, in the vicinity of the ATP binding site. Residue Glu183 localized within the conserved TGES loop was identified to play a key role in rutin-SERCA1 interaction (H-bond length of 1.7 Å), elucidating the ability of rutin to affect the affinity of SERCA1 to ATP. The binding of rutin in the proximity of Lys515 is likely to cause a decrease in FITC fluorescence.
Central European Journal of Medicine, 2006
α1 — adrenolytic activities of pyridoindole derivatives recently synthesized in the Institute of ... more α1 — adrenolytic activities of pyridoindole derivatives recently synthesized in the Institute of Experimental Pharmacology, Slovak Academy of Sciences, were measured. A characteristic set of derivatives (five active, one with a threshold activity and two inactive) was chosen and an elementary structure-activity study was performed. The structure and energy properties were estimated by quantum-chemical semiempirical AM1 and molecular mechanics methods. The ionization constants pKα of the individual derivatives were calculated by program Pallas or estimated by potenciometric titration. The α 1 blocking activities were measured by rat thoracic aorta model. The experimental model used was not α 1 — adrenoreceptor subtypes specific, however, the α 1D subtype could be considered to be a predominant type in a rat aorta. The obtained physico-chemical parameters were then compared with the blocking activities of the derivatives and following determining characters for α 1 — adrenolytic activ...