Computational investigation of the mechanism of the irreversible inhibition of the monoamine oxidase B enzyme

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.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