|
|
Interactions of drugs used to treat schizophrenia and their accompanying symptoms
Musilová, Jana ; Janoušek, Oto (referee) ; Cicková, Pavlína (advisor)
The thesis studies interactions and side effects of antipsychotic drugs. It describes the drug discovery and related scientific fields - especially the field of biological network analysis. The thesis also describes schizophrenia and its treatment. The aim of the work is creating script in R language for automatic data download from open source databases and a search of the most significant drug interactions in data from the open source databases, based on the visualisation and analysis of networks with Cytoscape software and its plugins, and a specification of similar pharmacological features of the most important medicaments.
|
|
|
Methods for Predicting Drug Side Effects in Silico
Cicková, Pavlína ; Lexa,, Matej (referee) ; Berka,, Karel (referee) ; Provazník, Ivo (advisor)
Vývoj a výzkum léčiv je oblastí současné vědy, jejíž nedílnou součástí je i využití výpočetních metod. Z důvodu nákladnosti a časové náročnosti laboratorních přístupů, metody in silico sehrávají svou významnou roli. I přes rychlý vývoj výpočetních technik využívaných při vývoji léků, však není drtivá většina zkoumaných molekul v procesu vývoje úspěšná a do schvalovací fáze nepostoupí. Nejen proto se nejmodernější strategie návrhu potenciálních nových léčiv zaměřují na opětovné zkoumání již schválených léků a berou do úvahy i analýzu podobností. Tato práce popisuje vývoj a aplikaci souboru několika workflow, jež byl vytvořen v rámci analytické platformy KNIME a jež implementuje metody strojového učení za účelem predikce nežádoucích účinků léčiv. Součástí prezentovaných workflow je získání dat, jejich předzpracování, výpočet metrik podobností a provedení explorační analýzy. Následně je využito klasifikačních modelů k predikci specifických nežádoucích účinků léčiv. Tato predikce vychází z principů technik založených na podobnosti. K natrénování modelů rozhodovacích stromů pro predikci potenciální asociace nežádoucích účinků s léčivy byly využity strukturní a jiné podobnosti schválených molekul léčiv. Hlavní přínos práce spočívá především v přenositelnosti použitých metod. Soubor workflow je určen k využití jako vhodný nástroj k řešení výzkumných otázek ohledně podobnosti léčiv a jelikož analytická platforma KNIME poskytuje uživatelsky přívětivé grafické rozhraní, není nutné, aby měli uživatelé pokročilé zkušenosti v oblasti strojového učení nebo programování, aby mohli soubor navržených workflow v rámci této platformy pro své analýzy využít.
|
|
|
SARS-CoV-2 methyltransferases as druggable targets
Kocek, Hugo ; Nencka, Radim (advisor) ; Bouřa, Evžen (referee)
Novel coronavirus (earlier referred to as "nCoV2019") became part of our lives in March 2020 and overnight turned everything upside-down. This virus is transmitted via respiratory droplets and causes respiratory diseases COVID-19 which can be severe and even fatal. So far, no effective treatment has been discovered and vaccination is our biggest hope thanks to its high efficacy. It is important to point out, that new mutations may possess problems and escape immunity induced by the vaccination. During the whole pandemic, many approved drugs were tested against SARS-CoV-2 (for example favipiravir, toremifene, and hydroxychloroquine) but none of those drugs showed to be effective against SARS-CoV-2 in clinical trials. The only approved antiviral drug is nucleotide analog remdesivir which showed significant efficacy against SARS-CoV-2 in clinical trials. However, timing and overall patient's health condition play a key role. Development of new antiviral drugs is necessary given the fact that this is the third time we face coronavirus with the potential to cause pandemic since the beginning of the 21st century. Therefore, it is likely that another new coronavirus will emerge. This thesis focuses on S-adenosylmethionine-dependent methyltransferases nsp14 and nsp16 from SARS-CoV-2 because they play a key...
|
|
|
Structural and functional analysis of cathepsin B1 from the blood fluke, Schistosoma mansoni
Jílková, Adéla ; Mareš, Michael (advisor) ; Obšil, Tomáš (referee) ; Mikeš, Libor (referee)
Schistosomiasis is a serious infectious disease that afflicts over 200 million people in tropical and subtropical regions. It is caused by Schistosoma blood flukes that live in human blood vessels and obtain nutrients from host hemoglobin, which is degraded by digestive proteases. Current therapy relies on a single drug and concern over resistance necessitates new drug development. In Schistosoma mansoni, cathepsin B1 (SmCB1) is a critical digestive protease that is a target molecule for therapeutic interventions. This thesis provides a comprehensive characterization of SmCB1 focused on structure-activity relationships and inhibitory regulation based on six crystal structures solved for SmCB1 molecular forms and complexes. SmCB1 is biosynthesized as an inactive zymogen in which the N-terminal propeptide operates as a natural intra-molecular inhibitor by blocking the active site. Detailed biochemical and structural analyses have identified a new and, so far, unique mechanism of SmCB1 zymogen activation through which the propeptide is proteolytically removed and the regulatory role of glycosaminoglycans in this process has been described. A study of SmCB1 proteolytic activity has revealed that the enzyme acts in two modes, as endopeptidase and exopeptidase, which makes it an efficient tool for host...
|
|
|
Molecular modelling in drug development
Kolář, Michal ; Hobza, Pavel (advisor) ; Vondrášek, Jiří (referee) ; Clark, Tim (referee)
Molecular modelling has become a well-established tool for studying biological mole- cules, moreover with the prospect of being useful for drug development. The thesis summarises research on the methodological advances in the treatment of molecular flexibility and intermolecular interactions. Altogether, seven original publications are accompanied by a text which aims to provide a general introduction to the topic as well as to emphasise some consequences of the computer-aided drug design. The molecular flexibility is tackled by a study of a drug-DNA interaction and also by an investigation of small drug molecules in the context of implicit solvent models. The approaches which neglect the conformational freedom are probed and compared with experiment in order to suggest later, how to cope with such a freedom if in- evitable. The noncovalent interactions involving halogen atoms and their importance for drug development are briefly introduced. Finally, a model for a faithful description of halogen bonds in the framework of molecular mechanics is developed and its per- formance and limits are tested by a comparison with benchmark ab initio calculations and experimental data. 1
|
|
|
Interactions of drugs used to treat schizophrenia and their accompanying symptoms
Musilová, Jana ; Janoušek, Oto (referee) ; Cicková, Pavlína (advisor)
The thesis studies interactions and side effects of antipsychotic drugs. It describes the drug discovery and related scientific fields - especially the field of biological network analysis. The thesis also describes schizophrenia and its treatment. The aim of the work is creating script in R language for automatic data download from open source databases and a search of the most significant drug interactions in data from the open source databases, based on the visualisation and analysis of networks with Cytoscape software and its plugins, and a specification of similar pharmacological features of the most important medicaments.
|
|
| |
guest ::
