Dissertation/ Thesis
Applications of theoretical and biophysical studies on rational drug design ; Εφαρμογές θεωρητικών και βιοφυσικών μελετών στον ορθολογικό σχεδιασμό φαρμάκων
| العنوان: | Applications of theoretical and biophysical studies on rational drug design ; Εφαρμογές θεωρητικών και βιοφυσικών μελετών στον ορθολογικό σχεδιασμό φαρμάκων |
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| المؤلفون: | Kiriakidi, Sofia, Κυριακίδη, Σοφία |
| بيانات النشر: | National and Kapodistrian University of Athens Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ) |
| سنة النشر: | 2021 |
| المجموعة: | National Archive of PhD Theses (National Documentation Centre Greece) |
| مصطلحات موضوعية: | Κβαντική χημεία, Ορθολογικός σχεδιασμός φαρμάκων, Μηχανισμός αντίδρασης, Φθορισμός, Μοριακή δυναμική, Καντεσαρτάνη, Υποδοχέας αγγειοτασίνης ΙΙ τύπου 1, Λιπιδικές διπλοστιβάδες, Χοληστερόλη, Quantum chemistry, Rational drug design, Reaction mechanism, Fluorescence, Molecular dynamics, Candesartan, Angiotensin II type 1 receptor, Lipid bilayers, Cholesterol, Χημεία, Φυσικές Επιστήμες, Φυσική και Θεωρητική χημεία, Chemical Sciences, Natural Sciences, Physical and Theoretical Chemistry |
| الوصف: | 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. ; Σε αυτή τη διατριβή μελετήθηκαν διάφορες πτυχές του ορθολογικού σχεδιασμού φαρμάκων, χρησιμοποιώντας μια πληθώρα υπολογιστικών τεχνικών. Αρχικά μελετήθηκε ο μηχανισμός κυκλοποίησης ενεργοποιημένων αλλενίων με καταλύτη σύμπλοκα του χρυσού, εφαρμόζοντας κβαντικούς υπολογισμούς. Τόσο ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| اللغة: | English |
| Relation: | http://hdl.handle.net/10442/hedi/48949 |
| DOI: | 10.12681/eadd/48949 |
| الاتاحة: | http://hdl.handle.net/10442/hedi/48949 https://doi.org/10.12681/eadd/48949 |
| Rights: | BY |
| رقم الانضمام: | edsbas.5A837246 |
| قاعدة البيانات: | BASE |
| DOI: | 10.12681/eadd/48949 |
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