Computational investigations of some pyrimidine nucleoside reverse transcriptase inhibitors

In this thesis, pyrimidine nucleoside analogue reverse transcriptase inhibitors are studied quantum chemically. The highly flexible nucleoside conformations are connected directly to their biological activities and anti-viral activities. The current work is aimed at investigating a series of nucleoside structures, from different conformational aspects, to reveal structural influences on various properties of nucleosides. Effects of nucleoside structures upon intramolecular interactions and chemical properties of nucleosides are investigated in three zidovudine (AZT) conformers. Three dimensional potential energy surfaces are generated for structure and energy explorations. It is found that intramolecular interactions and electronic properties are conformation-dependent, the evidence for which comes from spectroscopic studies (for example infrared and photoelectron), as well as Hirshfeld charge distribution analysis. In order to study solvent effects on the conformations and properties of nucleoside reverse transcriptase inhibitors, the solvent environment is taken into account in theoretical calculations. Solvent effects on the conformations and valence orbital structures of zidovudine are simulated in aqueous solutions. In a study of stavudine (d4T) conformers, solvents with different dielectric constants from small to large are applied to simulate various solvent environments with varied polarity. Solvent effects on geometries, vibrational spectra, and red/blueshifted infrared spectra due to intramolecular hydrogen bond interactions are further studied on stavudine. Small functional groups are used in drug design based on the strategy of bioisosterism. Some nitrogen-containing functional groups, such as amino and azide groups are commonly found in anti-HIV drugs. Inner shell ionization potentials of several nitrogen-containing functional groups in nucleoside analogues are predicted. The azide functional group (N3), a substitute of a hydroxyl group (OH) in AZT as a thymidine analogue, exhibits very different electronic properties than the hydroxyl group, but is found to play a key role in AZT as a chain terminator during the HIV virus replication process. Different responses of the structures and properties of the azide group are revealed by quantum chemical simulations when azide is attached to larger biomolecular and small organic species. The sugar ring conformation is another key topic in nucleoside research due to its correlations with the anti-viral properties of nucleoside drugs. Vibrational spectra, i.e. IR and Raman, are simulated in selected pyrimidine nucleoside analogues that display a wide range of sugar ring puckering conformations. The characteristic spectral peaks assigned to the particular sugar ring conformations are analyzed using vibrational spectroscopy. Finally, summary and outlook are given