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1

The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain

100%
Mazerski J., Muchewicz K.
Acta Biochimica Polonica
|
2000
|
tom 47
|
nr 1
Imidazoacridinones (IAs) are a new group of highly active antitumor compounds. The intercalation of the IA molecule into DNA is the preliminary step in the mode of action of these compounds. There are no experimental data about the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group should employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogues are presented. Each of the compounds was studied in two systems: i)in water, and ii)in the intercalation complex with dodecamer duplex d(GCGCGCGCGCGC)2. Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i)the chemical constitution of the side chain, and ii)the substituent in position8 of the ring system.
2

Termodynamiczne aspekty oddziaływania niskocząsteczkowych ligandów z DNA

81%
Jagiello K., Dopierala A., Mazerski J.
Postępy Biochemii
|
2010
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tom 56
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nr 3
3

The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: Molecular dynamics simulations

81%
Mazerski J., Martelli S., Borowski E.
Acta Biochimica Polonica
|
1998
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tom 45
|
nr 1
Intercalative binding of the antitumor drugs ametantrone and mitoxantrone to the dodecamer duplex d(CGCGAGCTCGCG)2 was studied by applying molecular dynamics in water with the GROMOS 87 force field. A number of reasonable binding orientations were tested by short pre-simulations. It was shown that in energetically favorable orientation the anthraquinone chromophore is perpendicular to the direction of inter-base hydrogen bonds. Helically shaped side-chains of the drugs fit to the minor groove. The best orientation obtained in pre-simulations was applied in the main simulations. Small but significant differences were found between structures of intercalation complexes of the two drugs with the dodecamer duplex, the mitoxantrone complex possessing more favorable energy. The molecular nature of interactions responsible for those differences has been discussed.
4

Glucosamine-6-phosphate synthase, a novel target for antifungal agents. Molecular modelling studies in drug design

81%
Wojciechowski M., Milewski S., Mazerski J., Borowski E.
Acta Biochimica Polonica
|
2005
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tom 52
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nr 3
Fungal infections are a growing problem in contemporary medicine, yet only a few antifungal agents are used in clinical practice. In our laboratory we proposed the enzyme L-glutamine: D-fructose-6-phosphate amidotransferase (EC 2.6.1.16) as a new target for antifungals. The structure of this enzyme consists of two domains, N-terminal and C-terminal ones, catalysing glutamine hydrolysis and sugar-phosphate isomerisation, respectively. In our laboratory a series of potent selective inhibitors of GlcN-6-P synthase have been designed and synthesised. One group of these compounds, including the most studied N3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid (FMDP), behave like glutamine analogs acting as active-site-directed inactivators, blocking the N-terminal, glutamine-binding domain of the enzyme. The second group of GlcN-6-P synthase inhibitors mimic the transition state of the reaction taking place in the C-terminal sugar isomerising domain. Surprisingly, in spite of the fact that glutamine is the source of nitrogen for a number of enzymes it turned out that the glutamine analogue FMDP and its derivatives are selective against GlcN-6-P synthase and they do not block other enzymes, even belonging to the same family of glutamine amidotransferases. Our molecular modelling studies of this phenomenon revealed that even within the family of related enzymes substantial differences may exist in the geometry of the active site. In the case of the glutamine amidotransferase family the glutamine binding site of GlcN-6-P synthase fits a different region of the glutamine conformational space than other amidotransferases. Detailed analysis of the interaction pattern for the best known, so far, inhibitor of the sugar isomerising domain, namely 2-amino-2-deoxy-d-glucitol-6-phosphate (ADGP), allowed us to suggest changes in the structure of the inhibitor that should improve the interaction pattern. The novel ligand was designed and synthesised. Biological experiments confirmed our predictions. The new compound named ADMP is a much better inhibitor of glucosamine-6-phosphate synthase than ADGP.
5

The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations

81%
Mazerski J., Antonini I., Martelli S.
Acta Biochimica Polonica
|
2000
|
tom 47
|
nr 1
Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i)in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.
6

Effect of transregional transport of pollutants on atmospheric air quality in the Tricity area of Poland

71%
Astel A., Mazerski J., Polkowska Z., Zygmunt B., Namiesnik J.
Polish Journal of Environmental Studies
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2003
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tom 12
|
nr 1
Two-dimensional variance analysis of the results of determination of NO₃⁻, SO₄²⁻, F⁻, Al³⁺, Cl⁻, NH₄⁺,PO₄³⁻, Fe³⁺, Ca²⁺, K⁺ and Mg²⁺, and pH and electrolytic conductivity of precipitation water samples collected in the Tricity area showed that transregional transport of pollutants affects air quality in this region. Over the large area of the Tricity agglomeration fluctuations in analyte concentrations in precipitation water samples are not affected on a statistically significant level by localizing sampling sites, but the area affected by transport direction of air mass movement.
7

N-methyl-N-D-fructosyl amphotericin B methyl ester [MF-AME], a novel antifungal agent of low toxicity: monomer-micelle control over selective toxicity

61%
Cybulska B., Gadomska I., Mazerski J., Grzybowska J., Borowski E., Cheron M., Bolard J.
Acta Biochimica Polonica
|
2000
|
tom 47
|
nr 1
Rational chemical modification of amphotericin B (AMB) led to the synthesis of sterically hindered AMB derivatives. The selected optimal compound, N-methyl- N-D-fructosyl amphotericin B methyl ester (MF-AME) retains the broad spectrum of antifungal activity of the parent antibiotic, and exhibits a two orders of magnitude lower toxicity in vivo and in vitro against mammalian cells. Comparative studies of MF-AME and AMB comprising the determination of the spectroscopic properties of monomeric and self-associated forms of the antibiotics, the investigation of the influence of self-association on toxicity to human red blood cells, and of the antibiotic-sterol interaction were performed. On the basis of the results obtained it can be assumed that the improvement of the selective toxicity of MF-AME could in part be a consequence of the diminished concentration of water soluble oligomers in aqueous medium, and the better ability to differentiate between cholesterol and ergosterol.
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