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Molecular modeling study of potential mycobacterial enoyl-reductase inhibitors
Slovák, František ; Holas, Ondřej (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Diplomate: František Slovák Supervisor: PharmDr. Ondřej Holas, Ph.D. Title of Diploma Thesis: Molecular modeling study of potential mycobacterial enoyl ACP reductase inhibitors. Tuberculosis is a worldwide spread infectious disease. The biggest problem of our time are completely and multi resistant strains of Mycobacterium tuberculosis that do not respond to currently known drugs. The main reason for high resistance and drug resistance is a bacillus composition of its cell wall. It contains a high proportion of mycolic acids. The synthesis of mycolic acids takes several steps. The final step is a catalytic reduction by enzyme enoyl - ACP reductase ( InhA ). This work was focused on finding new potential substances that would be able to inhibit this enzyme. There were used methods of computing and molecular modeling to search these substances. Adjusting of crystallographic structures ran in the program Maestro and docking in the MOE program. Over the 30 000 thousand molecules from the ZND (Zinc Natural Derivates) were tested by molecular docking on 3 crystallographic structures of InhA enzyme. 8 of these molecules were selected from this amount because their...
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Modulation of acetylcholinesterase activity using different organic compounds
Vavrošová, Petra ; Opletalová, Veronika (advisor) ; Holas, Ondřej (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Petra Vavrošová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of thesis: Modulation of acetylcholinesterase activity using different organic compounds Acetylcholinesterase is a vital enzyme because of its ability to end a nerve impulse by decomposition of neurotransmitter acetylcholin. Inhibitors of cholinesterases have been used in many sectors, such as drugs, pesticides, or substances abused as biological weapons. Using chosen agents an existence of acetylcholinesterase inhibition was detected together with its rate and character. The detection was accomplished by the method of measuring the decrease of acetylcholinesterase activity. In this experiment some organic solvents, metal salts, and other agents like gelatine, tacrine or caffeine were used. Ellman's spectrophotometrical detection was used to determine the decrease of acetylcholinesterase activity. The data were evaluated by the graphical representation by Dixon and Boltzmann. In this experiment the acetylcholinesterase from electric eel was used. Results showed that many chosen agents have the ability to inhibit acetylcholinesterase and on the other hand many of them do not have this...
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Polymeric stabilizers maintaining the supersaturation solubility of itraconazole nanocrystals after dissolution process
Kubačková, Jana ; Holas, Ondřej (advisor) ; Paraskevopoulos, Georgios (referee)
Title of thesis: Polymeric stabilizers maintaining the saturation solubility of itraconazole nanocrystals after dissolution process Author: Jana Kubačková Department: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Specialized supervisor: Assoc. Prof. Leena Peltonen, Ph.D. The increase of bioavailability of poorly water soluble drugs is still an issue. One of the techniques improving aqueous drug substance solubility, and consequently enhancing bioavailability, is formation of nanoparticles. However, the bioavailability is determined by the concentration of the dissolved drug achieved at the time of absorption. This fact emphasizes the importance of the maintenance of the high solubility until the absorption area is reached. Sufficiently stabilised nanocrystalline drugs offer a solution to this problem. In this thesis, the solid nanoparticle formations of an antifungal agent itraconazole (ITZ) are presented. Wet milling was employed to create the nanosuspension stabilised by binary mixture of stabilisers or by a single stabiliser. An aggregation inhibitor Poloxamer 407 (F127) in the combination with a polymeric precipitation inhibitor hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP) at different ratios, or a single precipitation inhibitor, were utilised. The...
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Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors
Šebl, René ; Zimčík, Petr (advisor) ; Holas, Ondřej (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND DRUG CONTROL Name: René Šebl Supervisor: Doc. PharmDr. Petr Zimčík,Ph.D Title of the thesis: Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors The topic of my thesis was synthesis of azaphtalocyanines containing pyrazinopyrazine units. These molecules have been published only in few publication till now. Since these molecules are extended by one pyrazine nucleuson each unit, their extended conjugation leads to an increased absorption in the higher regions of the absorption spectrum. In the first step, I focused on the synthesis of precursors for subsequent cyclotetramerization. Starting compound for the preparation of various precursors was 6,7- dichloropyrazino [2,3-b] pyrazine-2,3-dicarbonitrile. It underwent nucleophilic substitution leading to products substituted with various substiuents attached via heteroatoms such as oxygen or nitrogen. Another option is the condensation of 5,6-diaminopyrazine-2,3- dicarbonitrile with appropriate diketon. This attempt did not lead to the successful preparation of the precursor. The precursors were subsequently cyclotetramerized to corresponding macrocycles. We succeeded only with one precursor...
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Preparation of biodegradable nanoparticles for hydrophilic macromolecular drugs delivery
Szanyiová, Alexandra ; Holas, Ondřej (advisor) ; Dittrich, Milan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Consultant: PharmDr. Ondřej Holas, PhD. Student: Alexandra Szanyiová Title of thesis: Preparation of biodegradable nanoparticles for hydrophilic macromolecular drugs delivery This study investigates the formulation of nanoparticles containing hydrophilic macromolecular components (e.g. proteins). Selected material was PLGA based compounds synthesized at Department of Pharmaceutical Technology. As model compounds were used Rhodamine B, FITC labelled dextran and FITC labelled albumin. Selected methods of nanoparticles formulation were double-emulsion technique and nanoprecipitation. Prepared nanoparticles were purified by three cycles of centrifugation and encapsulation efficacy and recovery yield was measured. Effect of different polymers and stabilizers was followed. More specifically, the principal objective was to explore the differences between size, zeta potential and efficacy of encapsulation. Changes in these characteristics were brought about by the chosen polymers, stabilizers, encapsulated compound, length of centrifugation period. Prepared nanoparticles had size ranging between 150-474 nm and zeta potential approximately 30 mV. Even though the main goal of the study was to...
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Pyrazine derivatives as potential drugs V.
Horová, Anna ; Marek, Jan (advisor) ; Holas, Ondřej (referee)
Charles University in Prague, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Diplomate: Anna Horová Supervisor: PharmDr. Jan Marek, Ph.D. Title of Diploma Thesis: Pyrazine derivatives as potential drugs V. TBC is a specific world-wide infectious disease, compounded by increased migrations of people, the spread of HIV and the growth of MDR-TB, including extremely resistant strains. Precisely for the growth of MDR-TB resistant mycobacteria the work is focused on the preparation and development of other possible antituberculosis drugs (Pyrazine derivatives). Research into new medications lays emphasis on altering the effects of enzymes important for the vitality of mycobacteria. As part of my diploma thesis, pyrazine derivative modifications of clinical pyrazinamide medications were prepared. PZA is an important part of the short-term TBC treatment, having a sterile effect and the ability to work in an acidic environment and has a significant synergy with rifampicin. The small PZA molecule is a precursor to the pyrazine acid activated by pyrazinamide or nicotinamide. Hydrolysis of PZA in mycobacterial cells create Pyrazinecarboxylic acid (POA). In the experimental part, we have examined the variation molecules pyrazinamide and preparing the...
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Molecular modeling study of potential acetylcholinesterase inhibitors .
Kratochvíl, Jakub ; Holas, Ondřej (advisor) ; Marek, Jan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical chemistry and drug control Consultant: PharmDr. Ondřej Holas, Ph.D. Student: Jakub Kratochvíl Title of Thesis: Molecular modeling study of potential acetylcholinesterase inhibitors. This diploma thesis deals with an utilization of molecular docking to confirm the ability to inhibit acetylcholinesterase and butyrylcholinesterase in several substances. Well known AChE inhibitors (donepezil, tacrine, galanthamine, huperzine A) were chosen as ligands binding to active site of the enzyme. Their activity was confirmed. Other substances with certain inhibition potential were studied and in most cases the potential was proven. Structures of cholinesterases from human body and Torpedo californica were used for studies. The experimental part was carried out on a computer using a molecular modeling software: MGL Tools, PyMOL, Chimera and Autodock Vina.
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In silico screening of SIRT6 inhibitors
Kučera, Tomáš ; Doležal, Martin (advisor) ; Holas, Ondřej (referee)
Title: In silico screening of SIRT6 inhibitors Author: Tomáš Kučera Department: Department of Pharmaceutical Chemistry and Drug Control Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Specialized supervisor: Maija Lahtela-Kakkonen, Ph.D. Abstract: SIRT6 is called NAD-dependent protein deacetylase sirtuin-6 and it is a member of sirtuin protein family. It modulates acetylation of histone H3 (clinically important Lys9 and Lys56). The SIRT6 enzyme is an interesting drug target because of its role in DNA replication, glycolysis and inflammation - that is why the design of SIRT6 inhibitors is relevant in context of diabetes mellitus, arthritis and cancer. The aim of the work was to identify small molecules to inhibit deacetylase activity of SIRT6 using methods of computational chemistry and molecular modeling. We tried to find new lead structures with possibility to be optimized in next phases of the drug discovery process. The 9 known inhibitors and crystal structure of SIRT6 (PDB code 3K35) were used as input data during the modeling. Pharmacophoric and chemical similarity searches were selected from the group of ligand-based methods and molecular dock- ing from the group of structure-based methods. The pharmacophore was defined after structural alignment of four known ligands and tested on set of...
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Preparation and evaluation of lipid based nanoparticles as drug carriers
Kučerová, Kateřina ; Holas, Ondřej (advisor) ; Vraníková, Barbora (referee)
Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Consultant: Mgr. Jana Kubačková Student: Kateřina Kučerová Title of thesis: Preparation and evaluation of lipid based nanoparticles as drug carriers Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are promising drug delivery systems. Their capability to encapsulate both hydrophilic and lipophilic molecules, biocompatibility and biodegradability of lipids make them a suitable alternative for well-established drug carries. The aim of this thesis was to determine suitable ratios of composition of nanoparticles with acceptable properties (especially reduced size and polydispersity, high zeta potential absolute values), to investigate status and thermodynamic behaviour of the nanoparticles and lipids used and to examine drug encapsulation efficiency. Nanoprecipitation method was used to prepare nanoparticles from stearic acid as a solid lipid and in the case of NLC preparation isopropyl myristate as a liquid lipid was used. Kolliphor® P 188 as a surfactant and Span® 20 as a co-surfactant were the best choice to meet intended characteristics. It was shown that usually lower the concentration of surfactant and co-surfactant was the...
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Polymeric pharmaceutical nanoparticles preparation: a process optimization
Bárta, Michal ; Holas, Ondřej (advisor) ; Vraníková, Barbora (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical Technology Consultant: PharmDr. Ondřej Holas, Ph.D. Student: Michal Bárta Title of Thesis: Preparation of pharmaceutical nanoparticles: optimalization process Pharmaceutical, polymer nanoparticles besides others work as well as a drug carriers. Their uniqueness is not only because of their subcelular size, but as well because of the biodegradability and biocompatibility they hold. The benefit of these nanoparticiples is the possibility of creation of selective naoparticiples which are able to controle long-term release. The formulation of polymer nanoparticles can be reached within methods using preformed polymer or with polymerization of monomers. The main goal of my thesis was to optimize the production process of polymer nanoparticles and the observation of the solvent influences. The methods used for this reaserch were evaporation method and nanoprecipitation. Granulometric and electrical characteristics of particles were measured with Zetasizer ZS 90. Measurements have prooved, that it is preferable to use the nanoparticle method for the prepartion of the the small nanoparticles with low polydispersity and sufficient stability. From the results of the granulometric analysis of nanoparticles made by the...
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