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Computational Studies of Interactions of Small Molecules with their Biological Targets
Nekardová, Michaela ; Hobza, Pavel (advisor) ; Berka, Karel (referee) ; Kabeláč, Martin (referee)
The thesis specializes in the computational description of pharmaceutically important compounds. A substantial number of pharmaceutical drugs are small molecules that are bound to an active site of an enzyme by the "lock (binding site) and key (drug)" model through non-covalent interactions. The association of enzymes with drugs cause an increase or decrease in the activity of enzymes. The main topic is focused on the computational elucidation of the structural basis for the interactions of the purine-like compounds with the enzyme cyclin- dependent kinase 2 that belongs to the protein-kinase enzyme family. These enzymes play an important role in the cell cycle regulation; their increased activity significantly contributes to the loss of control over cell proliferation, which is one of the primary causes of cancer cell formation. The study describes the binding motifs of roscovitine, which shows an inhibitory effect on the function of cyclin-dependent kinases, and its analogues containing bioisosteric central heterocycles in the complex with cyclin-dependent kinase 2. The binding affinity between the cyclin-dependent kinase 2 enzyme and the inhibitors was quantified as calculated binding scores and evaluated in relation to the conformation of the optimized structures. The hybrid model combining the...
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Computational Studies of Interactions of Small Molecules with their Biological Targets
Nekardová, Michaela ; Hobza, Pavel (advisor) ; Berka, Karel (referee) ; Kabeláč, Martin (referee)
The thesis specializes in the computational description of pharmaceutically important compounds. A substantial number of pharmaceutical drugs are small molecules that are bound to an active site of an enzyme by the "lock (binding site) and key (drug)" model through non-covalent interactions. The association of enzymes with drugs cause an increase or decrease in the activity of enzymes. The main topic is focused on the computational elucidation of the structural basis for the interactions of the purine-like compounds with the enzyme cyclin- dependent kinase 2 that belongs to the protein-kinase enzyme family. These enzymes play an important role in the cell cycle regulation; their increased activity significantly contributes to the loss of control over cell proliferation, which is one of the primary causes of cancer cell formation. The study describes the binding motifs of roscovitine, which shows an inhibitory effect on the function of cyclin-dependent kinases, and its analogues containing bioisosteric central heterocycles in the complex with cyclin-dependent kinase 2. The binding affinity between the cyclin-dependent kinase 2 enzyme and the inhibitors was quantified as calculated binding scores and evaluated in relation to the conformation of the optimized structures. The hybrid model combining the...
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Nonclassical noncovalent interactions in proteins and their importance for design of novel specific viral enzyme inhibitors
Kříž, Kristian ; Lepšík, Martin (advisor) ; Novotný, Marian (referee) ; Kabeláč, Martin (referee)
Noncovalent interactions are vital for functioning of biological systems. For instance, they facilitate DNA base pairing or protein folding. Recently, in addition to classical noncovalent interactions such as hydrogen bond, nonclassical noncovalent interactions have been discovered. An example of these interactions is halogen bond belonging to the class of σ-hole interactions, the knowledge of which is already being useful for medical compound design. The aim of this work is to find out if the chalcogen bond, also a σ-hole interaction, plays a role in the binding of existing viral inhibitors, too. Following that, we are also interested whether or to what extent can these existing chalcogen bonds be optimized for a greater affinity of the inhibitor binding. Several protein-ligand crystal structures exhibiting geometrical properties favoring a chalcogen bond have been found in the PDB database. We examined the interaction energies and the interaction energy geometrical dependencies of model systems derived from these crystal structures by means of quantum chemical calculations. Further we have optimized their strength by a series of substitutions. We thus propose that chalcogen bond can become a player in rational design of inhibitors of viral enzymes and their protein target. Keywords: Noncovalent...
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Quantum Chemical Approach for In Silico Drug Design
Pecina, Adam ; Hobza, Pavel (advisor) ; Kabeláč, Martin (referee) ; Ettrich, Rüdiger (referee)
Computational approaches have become an established and valuable component of pharmaceutical research. Computer-aided drug design aims to reduce the time and cost of the drug development and also to bring deeper insight into the inhibitor binding to its target. The complexity of biological systems together with a need of proper description of non-covalent interactions involved in molecular recognition challenges the accuracy of commonly used molecular mechanical methods (MM). There is on the other side a growing interest of utilizing quantum mechanical (QM) methods in several stages of drug design thanks to increased computational resources. This doctoral thesis's topic is the QM-based methodology for the reliable treatement of intermolecular interactions. It consists of eight original publications devided into three topics and an accompanying text that aims to emphasize selected outcomes of the work. Firstly, the nature of nonclassical non-covalent interactions - so called σ-hole bonding - is studied by high-level QM methods. The strength and origin of halogen-, chalcogen- and pnicogen bonded model systems in extended datasets are accurately explored by coupled cluster QM method (CCSD(T)/CBS) and symmetry adapted perturbation theory (SAPT). The second part is devoted to three pharmaceutically...
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Vliv nepřímých daní na spotřebu cigaret v České republice
Kabeláč, Martin
This diploma thesis deals with description of influence of indirect taxes on consumption of cigarettes in the Czech Republic in 1993 - 2011. Analysed taxes are value added tax and excise. Influence of indirect taxes on consumption of cigarettes is examined by using of regression analysis. Than there is made recommendation of future taxation of cigarettes, which is based on results of the regression analysis. Recommendation should lead to increasing of budget revenues of the Czech Republic.
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