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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... |
