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doctoral thesis
Računalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B
Zagreb: University of Zagreb, Faculty of Science, 2021. urn:nbn:hr:217:053338
Tandarić, Tana
University of Zagreb
Faculty of Science
Department of Chemistry

Institutional repository: Repository of the Faculty of Science

Cite this document

Tandarić, T. (2021). Računalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B (Doctoral thesis). Zagreb: University of Zagreb, Faculty of Science. Retrieved from https://urn.nsk.hr/urn:nbn:hr:217:053338

Tandarić, Tana. "Računalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B." Doctoral thesis, University of Zagreb, Faculty of Science, 2021. https://urn.nsk.hr/urn:nbn:hr:217:053338

Tandarić, Tana. "Računalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B." Doctoral thesis, University of Zagreb, Faculty of Science, 2021. https://urn.nsk.hr/urn:nbn:hr:217:053338

Tandarić, T. (2021). 'Računalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B', Doctoral thesis, University of Zagreb, Faculty of Science, accessed 22 November 2024, https://urn.nsk.hr/urn:nbn:hr:217:053338

Tandarić T. Računalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B [Doctoral thesis]. Zagreb: University of Zagreb, Faculty of Science; 2021 [cited 2024 November 22] Available at: https://urn.nsk.hr/urn:nbn:hr:217:053338

T. Tandarić, "Računalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B", Doctoral thesis, University of Zagreb, Faculty of Science, Zagreb, 2021. Available at: https://urn.nsk.hr/urn:nbn:hr:217:053338

Metadata
TitleRačunalno istraživanje mehanizma ireverzibilne inhibicije enzima monoamin-oksidaze B
Title (english)Computational investigation of the mechanism of the irreversible inhibition of the monoamine oxidase B enzyme
AuthorTana Tandarić
MentorRobert Vianello (mentor)
Committee memberBranimir Bertoša (predsjednik povjerenstva)
Committee memberDarko Babić (član povjerenstva)
Committee memberIvan Kodrin (član povjerenstva)
GranterUniversity of Zagreb
Faculty of Science
(Department of Chemistry)
Zagreb
Defense date and country2021-02-19, Croatia
Scientific / art field,
discipline and subdiscipline		NATURAL SCIENCES
Chemistry
Universal decimal classification
(UDC)		54 - Chemistry. Crystallography. Mineralogy
Abstract
Monoamin-oksidaza B (MAO B) je flavoenzim koji regulira razinu endogenih i egzogenih amina u organizmu, uključujući neurotransmitere u mozgu. Predstavlja glavnu farmakološku metu u terapiji Parkinsonove i Alzheimerove bolesti. U sklopu ove disertacije proučen je mehanizam inhibicije MAO B ireverzibilnim selektivnim propargilaminskim inhibitorima, razagilinom i selegilinom te njihovim derivatima desmetilselegilinom i N-metilrazagilinom. Kvantno-kemijskom analizom unutar klasternog modela pokazano je da se inhibicija odvija u tri koraka. U prvom koraku, koji određuje ukupnu brzinu reakcije, flavinski kofaktor odcjepljuje hidridni ion s α-metilenske skupine supstrata. Dobiveni reakcijski profili i konačna struktura inhibiranog enzima u skladu su s eksperimentalnim podacima. Predloženi mehanizam dodatno je okarakteriziran empirijskim pristupom teorije empirijske valentne veze (EVB), koji uključuje cjelokupnu strukturu promatranog enzima. Simulacijama molekulske dinamike (MD) ispitane su termodinamika vezanja te interakcije inhibitora s aminokiselinama u aktivnom mjestu. Ostvareni rezultati od velike su važnosti za razvoj novih i efikasnijih MAO B inhibitora za kliničku primjenu.
Abstract (english)
Monoamine oxidase B (MAO B) is a flavoenzyme responsible for the regulation of exogenic and endogenic amine levels in the human body, including amine neurotransmitters in the brain. This enzyme represents a crucial pharmacological target for treating Parkinson's and Alzheimer's diseases. This dissertation elucidates the mechanism of the irreversible MAO B inhibition with clinical propargylamine inhibitors, rasagiline and selegiline, and their derivatives desmethyl-selegiline and methyl-rasagiline. The quantum-chemical analysis within the cluster model showed that this reaction proceeds in three steps, with the rate-limiting abstraction of the inhibitor's α-methylene H– anion by FAD in the first step. The obtained results are in excellent agreement with experimental observations. The proposed mechanism is further characterized by the Empirical Valence Bond approach on the entire enzyme structure, whereas molecular dynamics simulations identified residues crucial for the binding. The offered insight provides important guidelines for the development of new and more effective MAO B inhibitors.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:217:053338
Promotion2021
Study programmeTitle: Doctoral study in chemistry
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
Type of resourceText
Extent112 str. ; 30 cm
File originBorn digital
Access conditionsOpen access
Terms of useLicence In copyright icon
Created on2021-03-15 13:39:29