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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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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
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Accurate Quantum Mechanical Calculations on Noncovalent Interactions: Rationalization of X-ray Crystal Geometries by Quantum Chemistry Tools
Hostaš, Jiří ; Hobza, Pavel (advisor) ; Burda, Jaroslav (referee) ; Jurečka, Petr (referee)
There is a need for reliable rules of thumb for various applications in the area of biochemistry, supramolecular chemistry and material sciences. Simultaneously, the amount of information, which we can gather from X-ray crystal geometries about the nature of recognition processes, is limited. Deeper insight into the noncovalent interactions playing the most important role is needed in order to revise these universal rules governing any recognition process. In this thesis, systematic development and study of the accuracy of the computational chemistry methods followed by their applications in protein DNA and host guest systems, are presented. The non-empirical quantum mechanical tools (DFT-D, MP2.5, CCSD(T) etc. methods) were utilized in several projects. We found and confirmed unique low lying interaction energies distinct from the rest of the distributions in several amino acid−base pairs opening a way toward universal rules governing the selective binding of any DNA sequence. Further, the predictions and examination of changes of Gibbs energies (ΔG) and its subcomponents have been made in several cases and carefully compared with experiments. We determined that the choline (Ch+) guest is bound 2.8 kcal/mol stronger (calculated ΔG) than acetylcholine (ACh+) to self-assembled triple helicate rigid...
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Variational and perturbational calculations of interaction energies of noncovalent clusters
Hostaš, Jiří ; Hobza, Pavel (advisor) ; Fanfrlík, Jindřich (referee)
Calculation of noncovalent interactions in set of complexes containing halogen atom (called Halogensx10) is the main subject of this thesis. Wide variety of semiempirical quantum mechanical (SQM) methods (AM1, RM1, PM3, PM6 and SCC-DFTB augmented with empirical correction for dispersion interaction and hydrogen bonding (D3H4)) have been tested and their accuracy was discussed. The SCC-DFTB-D3H4 method showed the advantage of no artificial behaviour for other types of interactions with exception of halogen bonding which is underestimated. Specific correction for halogen bonding was designed as a purely empirical fix of serious underestimation of interaction energy in halogen bonded complexes that yields results for validation set very close to benchmark interaction energies with average error is 0.3 kcal/mol ~ 6% of the interaction energy. As a benchmark method the CCSD(T) extrapolated to the CBS limit, according to Helgaker's scheme with rather large correlation consistent basis sets has been used. The results presented herein can be used in the rational design of halogenated ligands as well as in research of another halogen enriched compounds.
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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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Side-chain Side-chain Interactions in Proteins
Berka, Karel ; Hobza, Pavel (advisor) ; Rulíšek, Lubomír (referee) ; Otyepka, Michal (referee)
Charles University in Prague Faculty of Science Department of Physical and Macromolecular Chemistry Side-chain Side-chain Interactions in Proteins Doctoral Thesis Abstract RNDr. Karel Berka Supervisors: Prof. Ing. Pavel Hobza, DrSc., FRSC RNDr. Jiří Vondrášek, CSc. Institute of Organic Chemistry and Biochemistry AS CR Center for Biomolecules and Complex Molecular Systems Praha 2009 2 Introduction Proteins are the most versatile and useful molecules in the cellular arsenal. They are the best catalysts the nature knows. Proteins cover the biggest amount of the cellular functions with range from metabolism and signaling through cell architecture to DNA replication. Variations of their structure and functions are amazing. And yet, they are built from simple building blocks - amino acids. Each amino acid has many possibilities of interactions with its neighborhood and the sequential context manifested through these possibilities is the main reason for the structure variability. The experimental investigation of the character and relative strength of interactions between amino acid residues is difficult. On the other hand, theoretical chemistry methods and techniques of are well suited for such task. They can provide useful information about structure, stability and nature of these interactions. The aim of the...
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Noncovalent Interactions in the Gas Phase and Aqueous Solution: Theoretical Study
Zendlová, Lucie ; Hobza, Pavel (advisor) ; Burda, Jaroslav (referee) ; Vondrášek, Jiří (referee) ; Jurečka, Petr (referee)
EAPUr rr|lclltal \ alLlť5' 5 Conclusions :, , . In the ia) part of present work we c intera cti on b etween u d"',il ". . . thy;';; il:'::: :íJTj.:lÍ' lI jl.#.ffiJ,lil itt8:"é'siia small number or*u.",7nJ organió solvent ňr"."i", (CH3.H, solvents yů[T"i^f.completely different interactions between the bases and the b"''" p.'"{ ;' "idilnn il#} il-t ÍT:!fl,-. i: : " o:] Y" .'h:.-S,t.* tu,", ot tt," moleóule Iuórc 'u'r' u property, and the'. .'l,'..,ťff,.'*lt'Lť':.lill:ilF.S'T!,l;situated above or belolthe !Á; ;;i. ;';;lě'"o ri," olašó ň"l"-.\,," ,, unique y"J::fiffii:x::. ."n'o*ison with otr,!. .otu"nt,, uň.'r,"í'ř;;.". are the In the ib) part_of present work based on the MD, SCC_DDFTB_D and ;"",'.Y|Tť'.#1.:."ffi i"T."lrJ'".r""u.'".XincorporateJ."-oŇTduplexwe i) Replacing nucleic acid base by modified nucleobase X leads.*:'] ,o Structural changes of the centrď -uuš"-pui. Gtu.tarrangement of central modified base pairs). ónli with ttresma'lest modified nucleobase p 'r'" Á.iJ.;;*;;.í' (A-P, P-T) stay planar. In the case 'of.B-T, Á-il.;';6 in specificorientation, one of the modified nuú"JÁ""x"*íto.""a outfrom DNA duplex. ii) Incre, .,""olr'iT"i1iTi1fi" or modified nucleobase X increases rhe iii) The highest s.ďectivity among- all base ana|ogue studied wasfound for modified nu"l"obus" O In the secono pu* of...
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Interaction of heteroboranes with biomolecules: Accurate quantum chemical study
Fanfrlík, Jindřich ; Hobza, Pavel (advisor) ; Fišer, Jiří (referee) ; Otyepka, Michal (referee) ; Vondrášek, Jiří (referee)
Charles University in Prague Faculty of Science Department of Physical and Macromolecular Chemistry Interaction of heteroboranes with biomolecules: Accurate quantum chemical study Doctoral Thesis Abstract RNDr. Jindřich Fanfrlík Advisor: Prof. Ing. Pavel Hobza, DrSc. Institute of Organic Chemistry and Biochemistry, AS CR Center for Biomolecules and Complex Molecular Systems Prague 2008 Univerzita Karlova v Praze Přírodovĕdecká Fakulta Katedra fyzikální a makromolekulární chemie Interakce heteroboranů s biomolekulami: kvantovĕ chemická studie Autoreferát disertační práce RNDr. Jindřich Fanfrlík Školitel: Prof. Ing. Pavel Hobza, DrSc. Ústav organické chemie and biochemie, AV ČR Centrum biomolekul a komplexních molekulových systémů Praha 2008 Introduction The world wide epidemic of AIDS is caused by two species of the human immunodeficiency virus (HIV-1 and HIV-2). Its 9200-bases-long RNA genome contains three main genes: gag, pol and env. The enzymes located within the pol gene (protease PR and reverse transcriptase RT) have become major targets for drug discovery, e.g. RT inhibitor Tenofovir disoproxil fumarate (DF) discovered by A. Holy at UOCHB in Prague and manufactured by Gilead Sciences and also already ten HIV-1 PR inhibitors (PIs) have been approved for use in the clinics: The evolution of drug...
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