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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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Optimalisation of preparation of biodegradable nanocarriers of drugs
Kvasnicová, Lucia ; Holas, Ondřej (advisor) ; Šnejdrová, Eva (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical technology Candidate: Mgr. Lucia Kvasnicová Consultant: PharmDr. Ondřej Holas Ph.D. Title of Thesis: Optimising the preparation of biodegradable drug nanocarriers The theoretical part was devoted to different types of nanoparticles, especially those which were prepared from poly(α-hydroxy acids). Other chapters were devoted to methods of their preparation- either from pre- prepared polymers or from directly polymerized monomers and the use of nanoparticles in medicine. The experimental part was aimed at optimizing the preparation of various derivates of poly(lactic-co-glycolic acid) (PLGA) using a nanoprecipitation method with medicated model drug. Rhodamine B was used as a model drug and poloxamer Pluronic® F127 was used as a stabilizer. The size of nanoparticles, their index of polydispersity (PDI) and the zeta potential were measured in the experimental part. Recovery yield, encapsulation efectivity and relative encapslation efectivity were also measured. The results showed that acetone was more suitable solvent than acetonitrile. The most appropriate weight of polymers was 20 mg, when the values of PDI were less than 0,2 and the size of nanoparticles was between 100 nm to 300 nm, so these samples had high...
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Formulation of freeze dried tablets for buccal application of vaccines
Vuová, Ngoc Lien ; Šklubalová, Zdeňka (advisor) ; Holas, Ondřej (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical Technology Mentor: Doc. PharmDr. Zdeňka Šklubalová, Ph.D. Student: Ngoc Lien Vuová Title of Thesis: Formulation of freeze dried tablets for buccal application of vaccines Mucosal vaccines represent an attractive way of vaccination with an advantage of inducing both systemic and local immunity. The aim of this diploma thesis was designing a composition of freeze-dried tablets for buccal administration of a model Bordetella pertusis vaccine. The easy removal from blister, firmness and aesthetic appearance as well as the appropriate taste and mucoadhesivity were the required product quality parameters. The excipients were characterised by differential scanning calorimetry, osmolality and pH measurement; the mechanical properties and disintegration time of freeze-dried tablets were evaluated. Among the variety of studied excipients and their combinations, dextran 40 as the main component of the preparation provided the best results. For the further modification of properties, the addition of fish gelatin, iota carrageenan and macrogol 300 is suitable. Freeze-dried tablets containing trehalose, mannitol and povidon 25 did not achieve the desirable quality parameters. Freeze- dried tablets containing iota carrageenan...
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Evaluation of rheological properties of terbinafine hydrochloride creams
Stehlíková, Dagmar ; Šnejdrová, Eva (advisor) ; Holas, Ondřej (referee)
CHARLES UNIVERSITY Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Candidate: Mgr. Dagmar Stehlíková Consultant: PharmDr. Eva Šnejdrová, Ph.D. Title of Thesis: Evaluation of rheological properties of terbinafine hydrochloride creams The aim of the rigorous work was to evaluate the rheological properties of creams with terbinafine hydrochloride at different stages of the formulation of a generic preparation using a suitable methodology and their comparison with the commercial preparation Lamisil 10 mg/g crm. (GlaxoSmithKline), which was specified as a standard. The theoretical part deals with the characterization of generic drugs, pharmaceutical and therapeutic equivalence. Tests suitable for measuring the flow properties of semi-solid preparations and evaluation methods are presented. The properties of terbinafine hydrochloride and the process of developing generic semi-solid formulations are summarized. Testing was performed at 25 řC on a Kinexus Pro+ rotational rheometer using cone-plate geometry. The flow properties of the creams were evaluated by nonequilibrium flow and viscosity curves, which were analysed by the power law model and Herschel-Bulkely model. The coefficient of consistency, the index of flow behaviour and the yield point were expressed. The...
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Study of the surfactants effect on polymer nanoparticle parameters
Moravcová, Katarína ; Holas, Ondřej (advisor) ; Šnejdrová, Eva (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Consultant: PharmDr. Ondřej Holas, PhD. Student: Katarína Kostíková Title of thesis: Study of the surfactants effect on polymer nanoparticle parameters The main aim of this Diploma thesis was to examine whether the use of various stabilizers has any effect on the resultant size of prepared nanoparticles and to find out which type of stabilizer is the most appropriate in terms of preparation of the nanoparticles of the necessary size, adequate polydispersity and steadiness. The preparation of nanoparticles was based on the use of sodium cholate as a surfactant and polymer PLGA (poly (lactid-co-glycolic acid)) consisting of monomers of lactic and glycolic acids. Nanoparticles were prepared by means of nanoprecipitation method. Sodium cholate solution has always been prepared in water in different concentration: 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, and 5%. The following have been used as stabilizers: poloxamer 407, polyvinyl alcohol, cetrimonium-bromide (CTAB), and polysorbate 20, all of them in concentration of 0.1% and sorbitan-monostearate in concentration of 0.01%. Measurement of the size of created nanoparticles was performed using the device Zetasizer at the...
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Preparation of polymeric fluorescent nanopyrticles
Širajová, Daniela ; Holas, Ondřej (advisor) ; Svačinová, Petra (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Consultant: PharmDr. Ondřej Holas, PhD. Student: Daniela Širajová Title of thesis: Preparation of polymeric fluorescent nanoparticles Nanoparticles based on biodegradable polyesters are a widely used platform for targeted drug delivery and subsequent controlled release. The aim of this diploma thesis was to prepare and optimize the preparation of polymeric nanoparticles with a fluorescent dye as a model substance. The nanoprecipitation method was used to prepare the nanoparticles. Nanoparticles prepared from two types of PLGA polymers (COOH terminated and ester terminated) were evaluated and compared. The surfactant and stabilizer were used in various concentration ratios to optimize the preparation. The surfactant was sodium cholate at concentrations of 0.1%, 0.5%, 1%, 2% and 5%. The nanoparticles were stabilized with Pluronic F-127 poloxamer at concentrations of 0.1%, 0.5% and 1%. Nanoparticles were compared in terms of encapsulation efficiency, particle size and zeta potential. In a dissolution experiment, the amount of fluorescein released was evaluated and compared as a function of time (48 hours) with acid-terminated PLGA and sodium cholate at concentrations of 0.1% and 2%....
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Development and characterization of modified polysulfone hemodialysis membranes by means of immobilized neutrophil elastase inhibitors
Morgošová, Kristína ; Kučera, Radim (advisor) ; Holas, Ondřej (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis University of Porto Faculty of Pharmacy Department of Chemical Sciences Department of Biological Sciences Candidate: Kristína Morgošová Supervisor: assoc. prof. PharmDr. Radim Kučera, Ph.D. Consultants: prof. Maria da Conceição Branco da Silva, Ph.D. prof. Maria Alice dos Santos Silva Gomes Martins, Ph.D. Susana Maria Santos Rocha, Ph.D. Title of diploma thesis: Development and characterization of modified polysulfone hemodialysis membranes by means of immobilized neutrophil elastase inhibitors. Chronic kidney disease (CKD) is a major health and financial burden, mainly because of the costly renal replacement therapy and treatment associated. The last stage, end-stage renal disease, is associated with high morbidity and mortality rate, generally due to cardiovascular complications. Chronic inflammation is frequently present in CKD patients, which is enhanced by the long term intra-dialytic recurrent contact between blood and hemodialysis (HD) membrane and further contributes to development of atherosclerosis. Contact with the artificial material of HD membranes leads to oxidative stress and neutrophil activation with release of neutrophil serine proteases such as human...
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