|
|
Optimization of Semiempirical Quantum Mechanical Methods for in Silico Drug Design
Kříž, Kristian ; Řezáč, Jan (advisor) ; Klimeš, Jiří (referee) ; Kolář, Michal (referee)
Optimization of Semiempirical Quantum Mechanical Methods for in Silico Drug Design Doctoral thesis Kristian Kříž The subject of this thesis is the optimization of semiempirical quantum mechanical methods (SQM) for their use in in silico drug design. The thesis covers two topics - COSMO2 solvation model optimization part and PLF547, PLA15 dataset development part. The first part is devoted to the optimization of COSMO solvation model by addition of a nonpolar term and reparametrization of the model for SQM methods PM6 and PM7. We have shown that the accuracy of the resulting "COSMO2" optimized model improved on all the tested datasets and we have compared it to other selected SQM solvation models. The method has also been tested on the protein ligand complexes as a part of a scoring function, where it provides better preditction of binding affinity of drug candidates for their target protein. The second part of the thesis describes the construction of datasets for noncovalent interactions aimed speicificly to represent an environment of an enyzme active site complexed with a ligand with reliable benchmark values of interaction energies in vacuum and solvent (water). The developed PLF547 and PLA15 datasets are suitable for testing and development of methods for the use in drug design. We have...
|
|
|
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...
|
|
|
The application of viral nanoparticles in biomedicine
Kříž, Kristian ; Španielová, Hana (advisor) ; Beranová, Jana (referee)
This work compiles studies that lead to new applications of viral nanoparticles with an emphasis on utilizations in biomedicine. Firstly the work follows the characteristics of viral nanoparticles and some general aspects of nanoparticles. Further described herein are exemplary studies that are using viral nanoparticles as a tool for the treatment of cancer, viral, bacterial or other diseases. This review also includes examples of researches leading to the usage of viral nanoparticles for diagnostic purposes. Lastly, studies in which viral nanoparticles served as nanoextractors, nanoreactors or nanotemplates for the synthesis of metal nanoparticles and galvanic cells are mentioned here too.
|
guest ::
RSS feed.