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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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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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Synthesis and biological evaluation of tacrine-amantadine derivatives
Král, Jan ; Opletalová, Veronika (advisor) ; Holas, Ondřej (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jan Král Supervisor: doc. RNDr. Veronika Opletalová, Ph.D. Consultant: PharmDr. Jan Korábečný, Ph.D. Title of diploma thesis: Synthesis and biological evaluation of tacrine-amantadine derivatives Alzheimer's disease (AD) is a fatal neurodegenerative disorder of brain. Nowadays there is only paliative treatment available, which can be further subdivided into two groups: acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist. Donepezil, rivastigmine and galantamine represents AChEIs currently available for AD treatment. Tacrine is the first AChEIs to be approved for AD treatment, however, it was withdrawn from the market due to its side effects, especially due to its hepatotoxicity. 7-Methoxytacrine (7-MEOTA) is less toxic tacrine derivative preserving pharmacological profile of tacrine. This diploma thesis describes synthesis of multifunctional 7-MEOTA- amantadine derivatives as potential drugs to confront AD. Using Ellmanʼs method, we have established their efficacy to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. All new synthesized hybrids from 7-MEOTA- amantadine family proved to be better...
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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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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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The Relationship between Structure and Activity of Potential Modulators of Acetylcholinesterase
Holas, Ondřej ; Opletalová, Veronika (advisor) ; Zimčík, Petr (referee) ; Patočka, Jiří (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Ondřej Holas Supervisor Doc. RNDr. Veronika Opletalová Ph.D. Title of Doctoral Thesis The relationship between structure and activity of potential modulators of acetylcholinesterase The Ph. D. thesis is focused on finding structure activity relationships for the acetylcholinesterase activity modulating compounds. Standard in vitro test using rat brain homogenate as the source of acetylcholinesterase was chosen for enzyme activity assay. Later, the procedure employing the colorimetric approach according to Ellman was developed. New procedure for inhibitory efficacy assessment based on Ellmanʼs method was designed as well. Aldoxime reactivators are mainly used as the causal antidotes of organophosphorus compounds intoxications. Organophosphorus compounds are widely used for agricultural purposes as pesticides, and in the industry as a plasticizers or flame retardants. Beside the peaceful purposes, they were also developed as nerve agents applicable for chemical warfare. Toxic mechanism of the compounds is formation of covalent bond with serine (Ser203) hydroxyl in active site of acetylcholinesterase. Unfortunately, none of the currently used reactivators is able...
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The relationship between structure and activity of potential reactivators of acetylcholinesterase I.
Holas, Ondřej ; Opletalová, Veronika (advisor) ; Pohanka, Miroslav (referee)
The realtionship between structure and activity of potencial reactivators of acetylcholinesterase Organophosphorus compounds (OPC) are used as agricultural pesticides and in industry as fire retardants or plastificators. For military use there have been developed nerv agents (NA, e.g. tabun, sarin, somna, VX). The toxicity of these compounds is based upon phosphorylation or phosphonylation at the serine hydroxy group (Ser200) of the active site of the acetylcholinesterase. The current standard treatment consists of administration oxime reactivators in combination with anticholinergic drug (preferably atropin). Unfortunately, none from the currently used oximes is sufficiently effective against all types of the OPCs. The aim of this study is determination of the relationship between structure and activity of new reactivators against paraoxon inhibited AChE in vitro and comparison with currently available substances. For evaluation of reactivation activity has been chosen standard in vitro test using rat brain homogenate
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Delivery of protein or peptide into the skin using cubosomes and microneedles
Pekáčová, Simona ; Pávek, Petr (advisor) ; Holas, Ondřej (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Simona Pekáčová Supervisor: Prof. PharmDr. Petr Pávek, Ph. D. Title of diploma thesis: Delivery of protein or peptide into the skin using cubosomes and microneedles Transdermal transport of high-molecular-weight and hydrophilic substances is complicated by the protective skin layer, the stratum corneum. Physical breaching of this layer using microneedles combined with penetration- enhancing properties of cubosomes was previously reported as an effective approach to transdermal drug delivery and therefore employed in this project. (Rattanapak et al. 2012) Delivering abilities of solid (600 µm), coated (500, 600, 750 µm) and hollow (450, 600 µm) MNs were compared with intradermal injection by hypodermic needle. Cubosomes were prepared from phytantriol, poloxamer 407 and propylene glycol using liquid precursor method and loaded with fluorescent ovalbumin (FL-OVA) or SIINFEKL-TAMRA (ST) peptide. Several formulations for coating of solid microneedles were prepared using various solvents and excipients to investigate quality of coatings and their ability to deliver the drug into skin. Polyvinyl alcohol (PVA) turned out to be the most efficient coating excipient providing equally spread...
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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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Impact Analysis of Music Events of Selected Beverage Brands
Holas, Ondřej ; Postler, Milan (advisor) ; Obdržálek, Lukáš (referee)
The thesis Impact Analysis of Music Events of Selected Beverage Brands describes the way certain beverage companies use music events to communicate with customers and how event marketing contributes to raising public awareness. The theoretical part focuses on marketing and commercial communication and also on event marketing and its relation to a brand. In the practical part, which is based on a research conducted by means of a questionnaire, the impact of events on end consumer's brand perception is analysed. This analysis is accompanied by an expert interview with a Jägermeister representative, followed by opinions of other professionals who give their point of view.
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