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Interaction of proteins with inhibitors: quantum chemical study
Dobeš, Petr ; Hobza, Pavel (advisor) ; Vondrášek, Jiří (referee) ; Jurečka, Petr (referee)
This dissertation focuses on theoretical studies of the interaction between protein kinases and their inhibitors. Studied protein kinases, cyclin-dependent kinase 2 (CDK2) and CK2 kinase (casein kinase 2) play an important role in regulating cellular processes in eukaryotic organisms. Their abnormal function in human cells can lead to serious diseases. This process can be stopped by blocking the aberrant protein kinases using specific low molecular weight inhibitors. Inhibitors of protein kinases typically bind to the active site of the enzyme by noncovalent interactions. Theoretical description of these interactions using quantum-chemical and molecular mechanical methods can help in understanding the biophysical principles governing the binding. These, in turn, can be subsequently used for a rational drug design of more effective and more specific inhibitors. The stabilization energy of the complex of CDK2 with inhibitor roscovitine is predominantly formed by the dispersion energy. DFT methods, which do not describe the dispersion energy was thus completely inappropriate for the treatment of such a system. When an empirical term is included to correct for the description of dispersion, such methods, as e.g. the SCC-DFTB-D, can be recommended for computation of this or similar complexes. The dominant part...
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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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Φύσις of Ionian thinkers
Kočandrle, Radim ; Kratochvíl, Zdeněk (advisor) ; Bouzek, Jan (referee) ; Hobza, Pavel (referee)
ÓÓo16 of the lonian thinkers Radim Kočandrle Ph.D. Dissertation- suÍnmarv The thesis aims to investigate the notion of tpóotg within the context of the early philosophy.The regulartranslationof thetermqÓotg is nature.Generally,the notionof góotg is consideredto play a central role in the way of thinking that originatedin Ionian Miletus. Thereforetheconceptof góotg is essentialfor theearlyphilosophy_ doxographywouldlater interpretthis period as the period of the ',inquiryinto nature..,iotopíct.nepi rpóoe<rlg;and almostallthe earlyphilosopher'swritingswouldbe calledIIep|qóoecoq"The thesis,however, dealsmerelywith the oldestconceptions.It concentrateson the notionof qóotg of the two Ionianphilosophers,namelyAnaximanderof Miletus and Heraclitus,the Ephesian.The set of fragmentsby Anaximandercontainsthe oldestdřect philosophicalfragmentsto be preserved. While in Heraclitus,thereis the frst occurrenceof the word tpóotq to be documentedin the historyof philosophy.Furthermore,thepre-philosophicaluseof the notionqóotg by Homer is alsodiscussed,sinceit impliessomenotableobservationsfor thedevelopmentof thenotion. The substantialpart of theinvestigationis formedup by thecritical reflectionof theauthors who mediatedtherelevanttext records.Such a criticalapproachis fundamentalfor studying Milesians especially.Their...
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