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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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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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Theoretical Study of Non-covalent Interaction from small molecules to Biomolecules
Haldar, Susanta ; Hobza, Pavel (advisor) ; Havlas, Zdeněk (referee) ; Jurečka, Petr (referee)
xv Abstract The aim of this thesis is to investigate the accurate stabilization energy and binding free energy in various non-covalent complexes spanned from small organic molecules to biomolecules. Non-covalent interactions such as H-bonds, π...π stacking and halogen bonds are mainly responsible for understanding of most biological processes, such as small molecule interactions with surface, protein-ligand binding in the cell machinery, etc. In the thesis, different non-covalent complexes such as graphene…electron donor- acceptor complexes, DNA base pair interaction with silica surface, etc, were investigated. The reference stabilization energies were calculated at ab initio level, e.g., CCSD(T)/CBS method wherever possible. On the other hand, more approximated scaled MP2 method (MP2.5/CBS/6-31G*(0.25)) is taken as reference instead of CCSD(T)/CBS due to the size of the complexes. Further, the DFT and MM energies were also tested towards the reference one. The knowledge of non- covalent interaction is required for rationalizing of any association processes in nature which requires accurate description of the free energy change. The state-of- the-art molecular dynamics simulation in full atomic scale and biased metadynamics free energy method is used for binding free energy calculations. The well tempered...
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Quantum-chemical study of noncovalent interactions
Sedlák, Róbert ; Hobza, Pavel (advisor) ; Havlas, Zdeněk (referee) ; Černušák, Ivan (referee)
The aim of this thesis is to investigate strength and origin of the stabilization for various types of noncovalent interactions. As this knowledge could lead to a deeper understand- ing and rationalization of the binding phenomena. Further, to participate on the de- velopment of new noncovalent data sets, which are nowadays inevitable in the process of parametrization and validation of new computational methods. In all the studies, different binding motifs of model complexes, which represent usually crystal structures, structures from unrelaxed scans or the local minima, were investi- gated. The calculations of the reference stabilization energies were carried out at ab initio level (e.g. CCSD(T)/CBS, QCISD(T)/CBS). Further, the accuracy of more ap- proximate methods (e.g. MP2.5, DFT-D or SQM methods) toward reference method, was tested. In order to obtain the nature of the stabilization the DFT-SAPT decompo- sition was frequently utilized. In the first part of the thesis, the importance and basic characteristics of different types of noncovalent interactions (e.g. halogen bond, hydrogen bond, π· · · π interaction etc.), are discussed. The second part provides the description of computational methods which were essential for our investigation. The third part of the thesis provides an overview for part...
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