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, P. K. ; Roy , K. Chemometr. Intell. Lab. 2011 , 109 , 146 . 10.1016/j.chemolab.2011.08.007 20. Snedecor , G. W. ; Cochran , W. G. Statistical Methods ; Oxford & IBH : New Delhi , 1967 . 21. Marshall , G. R. In 3D QSAR in Drug

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References 1 Bodor N, Buchwald P. Retrometabolic drug design and targeting. John Wiley & Sons, New York, NY, 2012. ISBN 978

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Baldwin JJ, Lumma WC Jr, Lundell GF, et al. Symbiotic approach to drug design: antihypertensive beta-adrenergic blocking agents. J Med Chem. 1979; 22: 1284–1290. 10 Clifton JE

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Abstract  

Modern thermal analysis, microcalorimetry and new emerging combined techniques which deliver calorimetric, microscopic and spectroscopic data offer a powerful analytical battery for the study of pharmaceuticals. These techniques are very useful in all steps of development of new drug products as well as methods for quality control in production. The characterization of raw materials enables to understand the relationships between polymorphs, solvates and hydrates and to choose the proper development of new drug products with very small amount of material in a very short time. Information on stability, purity is valuable for new entities as well as for marketed drug substances from different suppliers. Excipients which vary from single organic or inorganic entity to complexes matrixes or polymers need to be characterized and properly controlled. The thermodynamic phase-diagrams are the basis of the studies of drug-excipients interactions. They are very useful for the development of new delivery systems. A great number of new formulations need proper knowledge of the behaviour of the glass transition temperature of the components. Semi-liquid systems, interactions in aqueous media are also successfully studied by these techniques.

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Orvosi Hetilap
Authors: Veronika Urbán S., Elizabeta Benevolenskaya, Judit Kiss, Bernadett Sági, Beáta Hegyi, and Ferenc Uher

Hamm, C. A., Costa, F. F.: The impact of epigenomics on future drug design and new therapies. Drug Discov. Today, 2011, 16 , 626–635. Costa F. F. The impact of epigenomics on future

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Abstract  

The influence on the melting of calf thymus DNA induced by cationic liposomes, commonly used in gene therapy, was studied by means of ultraviolet spectrophotometry and differential scanning calorimetry. Both the two methods reveal that DNA in DNA-induced liposome complexes undergoes a denaturation process at a much higher temperature than free DNA does. The extent of protection strongly depends on the charge ratio R(+/−) of liposome-DNA complexes. In the case of dioleoyl trimethyl ammonium propane (DOTAP) liposomes, the maximum of the stabilization occurs at R(+/−)=0.7, where the DNA is still native up to temperatures higher than 100°C. This protection against denaturation up to higher temperatures might be of importance for bio-technological applications, such as biomolecular separation, antigene sequencing and for drug design purpose.

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N.P. Gensmantel , Physicochemical Properties and Drug Design. In: F.D. King (Ed.) Medicinal Chemistry: Principles and Practice, Royal Society of Chemistry, Cambridge, 2001, pp. 98

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Acta Microbiologica et Immunologica Hungarica
Authors: Nóra Gyémánt, Annamária Molnár, Gabriella Spengler, Yvette Mándi, Margit Szabó, and J. Molnár

Various bacterial plasmids can be eliminated from bacterial species cultured as pure or mixed bacterial cultures by non-mutagenic heterocyclic compounds at subinhibitory concentrations. For plasmid curing, the replication should be inhibited at three different levels simultaneously: the intracellular replication of plasmid DNA, partition and intercellular transconjugal transfer. The antiplasmid action of the compounds depends on the chemical structure.  The targets for antiplasmid compounds were analysed in detail. It was found that amplified extrachromosomal DNA in the superhelical state binds more drug molecules than does the linear or open-circular form of the plasmid or the chromosome, without stereospecificity which leads to functional inactivation of the extrachromosomal genetic code. Plasmid elimination also occurs in ecosystems containing numerous bacterial species simultaneously, but the elimination of antibiotic resistance-encoding plasmids from all individual cells of the population is never complete.  The medical significance of plasmid elimination in vitro is, it provides a method to isolate plasmid-free bacteria for biotechnology without any risk of mutations, and it opens up a new perspective in rational drug design against bacterial plasmids.  Hypothetically, the combination of antiplasmid drugs and antibiotics may improve the effectivity of antibiotics against resistant bacteria; therefore, the results cannot be exploited until the curing efficiency reaches 100%. Inhibition of the conjugational transfer of antibiotic resistance plasmids can be exploited to reduce the spreading of these plasmids in ecosystems.

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Various bacterial plasmids can be eliminated from bacterial species cultured as pure or mixed bacterial cultures by non-mutagenic heterocyclic compounds at subinhibitory concentrations. For plasmid curing, the replication should be inhibited at three different levels simultaneously: the intracellular replication of plasmid DNA, partition and intercellular transconjugal transfer. The antiplasmid action of the compounds depends on the chemical structure.  The targets for antiplasmid compounds were analysed in detail. It was found that amplified extrachromosomal DNA in the superhelical state binds more drug molecules than does the linear or open-circular form of the plasmid or the chromosome, without stereospecificity which leads to functional inactivation of the extrachromosomal genetic code. Plasmid elimination also occurs in ecosystems containing numerous bacterial species simultaneously, but the elimination of antibiotic resistance-encoding plasmids from all individual cells of the population is never complete.  The medical significance of plasmid elimination in vitro is, it provides a method to isolate plasmid-free bacteria for biotechnology without any risk of mutations, and it opens up a new perspective in rational drug design against bacterial plasmids.  Hypothetically, the combination of antiplasmid drugs and antibiotics may improve the effectivity of antibiotics against resistant bacteria; therefore, the results cannot be exploited until the curing efficiency reaches 100%. Inhibition of the conjugational transfer of antibiotic resistance plasmids can be exploited to reduce the spreading of these plasmids in ecosystems.

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Alzheimer's disease (AD) related beta amyloid (Aβ) peptides possess high propensity towards aggregation. Their diffusion-controlled association follows a physico-chemically well-defined kinetics: the fibrillization starts from the monomeric/ dimeric state, and proceeds in the direction of oligomeric→protofibrillar→ fibrillar state producing neurotoxic aggregates. Nowadays one of the major directions of the drug design against AD is the synthesis of putative amyloid aggregation inhibitor molecules (AAI) which are able to hinder the formation of these toxic amyloid aggregates. Studies of both the Aβ aggregation and the effect of the AAIs on this process can be performed with several instrumental techniques. The size distribution of the aggregates up to the micron size range can be characterized with dynamic light scattering (DLS). On the other hand, species having a diameter above 5 nm can be visualized with transmission electron microscopy (TEM). In this work, we propose standardized sample preparation protocols in order to gain a reproducible aggregation profile of the Aβ peptides according to the experimental requirements. Besides, we investigate the effect of our formerly designed AAI, the RIIGLa pentapeptide on the aggregation of Aβ[1-42]. Based on our DLS and TEM results, we demonstrate the aggregation altering ability of this pentapeptide.

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