Dissertation committee:
Thomas Mavromoustakos, Professor, National and Kapodistrian University of Athens, Athens, Greece
Carlos Silva Lopez, Professor, University of Vigo, Vigo, Spain
Demeter Tzeli, Associate Professor, National and Kapodistrian University of Athens, Athens, Greece
Zoe Cournia, Senior Researcher - Associate Professor Level, Biomedical Research Foundation, Academy of Athens
Andreas Tzakos, Associate Professor, Univeristy of Ioannina, Ioannina, Greece
Athanasios Gimisis, Professor, National and Kapodistrian University of Athens, Athens, Greece
Georgia Melagraki, Assistant Professor, Hellenic Military Academy. Athens, Greece
Summary:
In this thesis, several aspects of rational drug design were studied by employing a plethora of computational techniques. Initially, the gold catalyzed cyclization mechanism of functionalized allenes was studied, by implementing quantum chemistry calculations. Both allenic moieties and their derivatives are used as drug building blocks in a wide variety of pharmaceutical categories, due to their reactivity and stereoselectivity. The next aim of this study was the fluorescence mechanism investigation of a novel theranostic device with the use of excited state quantum chemistry. In particular, a gemcitabine analogue which shows fluorescence as a prodrug was studied, allowing for the real-time observation of the drug delivery while when it is in the tumour environment, it releases the cytotoxic drug along with a fluorescent mark. Our theoretical results correctly predicted the above mechanism and were confirmed by preliminary fluorimetry assays. Finally, the drug binding mechanism of candesartan to AT1R was studied in this thesis, with the use of Molecular Dynamics. We observed that in pure DPPC bilayers candesartan approaches the receptor through the lipid membrane (indirect mechanism) while the extracellular entrance of the receptor (direct mechanism) is blocked by its N-terminus. When complex lipid membranes were modelled with 40% of cholesterol, our simulations showed that cholesterol binds the receptor in a special area characterized as Cholesterol Consensus Motif. The binding of cholesterol induces allosteric modulations on the receptor, resulting in a more accessible extracellular entrance while the ordering that induces on the lipid bilayer delays candesartan lateral diffusion to the receptor, through the lipid membrane.
Keywords:
quantum chemistry, reaction mechanism, fluorescence, molecular dynamics, candesartan
