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  • Suomivuori, Carl-Mikael (2014)
    Mobile zinc is involved in the pathogenesis of several fatal neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Design of novel Zn(II) chelators is a promising research field in the development of new medical treatments for these diseases. However, depletion of zinc using a high affinity chelator can lead to cell death. The Zn(II) chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) can reverse some zinc related pathologies, but its high zinc affinity makes it unsuitable for use as a medical treatment. In this thesis, calculations at the density functional theory (DFT) level have been performed on TPEN and TPEN derivatives. The aim was to suggest modifications in the molecular structure which lower the zinc affinity of the chelator to a less toxic level, and which therefore could potentially lead to new medical therapies for neurodegenerative diseases. A further aim was to develop a computational protocol that is suitable for studies and in silico design of Zn(II) chelators. The results show that DFT methods, which include a correction for dispersion forces and which treat the solvent implicitly, can yield free energies for ligand exchange reactions which agree well with experimental data. The employed computational methodology is also suitable for similar studies involving other metals. The zinc affinity of TPEN can be lowered by substituting hydrogens on its pyridyl rings with electron-attracting groups. Substitution with weakly electron-donating groups can also lower the zinc affinity, provided that it results in a conformational change which stabilises the free chelator. Substitution of carbon atoms with nitrogens on the pyridyl rings also lowers the zinc affinity. The computational methodology needs improvement if one wishes to address more complicated problems, such as studies of complexation energies for chelators with varying denticities, in which solvent molecules may play a more significant role as one of the ligands.