diplomsko delo univerzitetnega študijskega programa I. stopnje
Marko Breznik (Author), Urban Bren (Mentor), Janez Konc (Co-mentor)

Abstract

Klinična depresija je poglaviten vzrok invalidnosti in pomemben dejavnik tveganja za samomor, ki je nadpovprečno pogost vzrok smrti v Sloveniji. Kljub zahtevnosti se motnja lahko zdravi uspešno in ima dobro prognozo. Antidepresivi se za zdravljenje depresije in drugih motenj uporabljajo vse pogosteje; navkljub obsežnim raziskavam pa za ta zdravila še vedno obstajajo številne možnosti izboljšav. Antidepresivi iz skupine reverzibilnih inhibitorjev monoamin-oksidaze A (RIMA) so bili doslej zapostavljeni zaradi pogostega enačenja s skupino antidepresivnih zdravil, ki so se na encim monoamin-oksidazo (MAO) vezali ireverzibilno in s tem povzročali smrtno nevarne interakcije s hrano. RIMA predstavljajo drugo generacijo antidepresivov z encimskim delovanjem in teh interakcij ne povzročajo, prav tako imajo bistveno zmanjšano tveganje interakcij z drugimi zdravili. Na osnovi dobre učinkovitosti, varnosti, ugodnega profila stranskih učinkov ter pomanjkanja predstavnikov te skupine na trgu, smo se v diplomskem delu osredotočili na racionalno načrtovanje antidepresivov tipa RIMA. Harmin je naravna spojina s tradicionalno rabo kot RIMA. Po strukturi predstavlja majhno, rigidno molekulo z dobro absorpcijo, penetracijo krvno-možganske pregrade in nanomolarno inhibitorno koncentracijo MAOA, vendar zaradi pomanjkanja selektivnosti delovanja povzroča številne stranske učinke. Reševanja problematike smo se lotili po treh pristopih. Zdravilom-podobne substance smo razvrstili po strukturni podobnosti derivatu harmina, ki tvori dodatne interakcije v lipofilnem žepku aktivnega mesta in ima in vitro izboljšano afiniteto za MAOA. Najbolj podobne molekule smo sidrali v tarčo in jih razvrstili po oceni vezavne energije. Kot rezultat prvega pristopa navajamo 100 tarči najbolje prilegajočih se molekul, za katere lahko pričakujemo spremembe v delovanju na sekundarnih mestih; vezava na MAOA pa je (vsaj in sillico) ohranjena. Struktura 15 najboljših ujemanj prvega pristopa nakazuje dobre farmakokinetične lastnosti. Iz njih smo vzeli fragmente, ki segajo v lipofilni žepek, ter jih inkorporirali na ogrodje harmina. S tem smo pridobili nabor strukturnih derivatov harmina za bodoče in vitro študije in obogatili znanje o povezavi struktura-aktivnost za RIMA. Za derivate harmina, ki so rezultati drugega pristopa, predvidevamo izboljšano vezavo in s tem povezano višjo selektivnost delovanja. Zadnji pristop pa je temeljil na iskanju ligandov iz drugih podobnih kristalnih struktur na redefiniranem vezavnem mestu. Priporočene so variante uporabe in usmerjenega razvoja harmala alkaloidov v druge zdravstvene namene. Zlasti inovativno je zdravljenje Downovega sindroma in Alzheimerjeve bolezni z inhibicijo DYRK1A-kinaze.

Keywords

harmin;zaviralci;antidepresivi;racionalno načrtovanje;monoamin-oksidaza;diplomske naloge;

Data

Language: Slovenian
Year of publishing:
Typology: 2.11 - Undergraduate Thesis
Organization: UM FKKT - Faculty of Chemistry and Chemical Engineering
Publisher: [M. Breznik]
UDC: 544.475:547.944.8(043.2)
COBISS: 20692758 Link will open in a new window
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Other data

Secondary language: English
Secondary title: Rational design of reversible monoamine oxidase A inhibitors
Secondary abstract: Depression is the single leading cause of disability worldwide. It represents a significant risk factor for suicide - a remarkably common preventable cause of death in Slovenia. Despite its complexity, the disorder can be treated successfully with the use of antidepressants. Although antidepressants have been studied extensively; possibilities for improvement remain. Reversible inhibitors of monoamine oxidase A (RIMA) represent a hardly-ever used class of antidepressants, since they are often equated to one of the first generations of antidepressants – the “classical” irreversible monoamine oxidase inhibitors (MAOI). The classical MAOI covalently bind to the enzyme, causing life-threatening drug-food interactions. RIMA represent the second generation of MAO-acting antidepressants that pose a significantly lower drug interaction threat. Due to their robust efficacy, safety, and favorable side effect profile, as well as the lack of representatives on the market, we focused on the rational drug design of RIMA-type antidepressants. Harmine is a natural compound traditionally considered a RIMA. It is a small, rigid compound that exhibits good gastrointestinal absorption, good penetration of the blood-brain barrier, and a nanomolar MAOA inhibitory concentration. However, it causes various side effects due to low target selectivity. This problem was tackled by several approaches. A collection of drug-like substances was rated by structural resemblance to a harmine derivative that forms additional interactions with the harmine-unoccupied lipophilic pocket in the MAOA binding site and exhibits an improved affinity towards MAOA in vitro. Structurally similar compounds were docked in the target protein and rated by binding energy estimates. The resulting 100 top-rated molecules show a vast structural diversity. Their activity at secondary physiological sites is expected to be altered, while MAOA-affinity remains preserved in silico. Structural indicators of pharmacological properties were examined for the 15 top-fitting molecules of the first approach. The fragments reaching into the lipophilic pocket were collected and incorporated onto the harmine scaffold. A collection of harmine derivatives was proposed for the in vitro evaluation and further studies of the structure-activity relationship. Additionally, the possibility of using the targeted development of harmala alkaloids for other medical purposes was highlighted. Particularly innovative is the option of treating Down's syndrome or Alzheimer's disease using harmine-based DYRK1A-kinase inhibitors.
Secondary keywords: harmine;inhibitors;antidepressant;rational design;in silico;monoamine oxidase;MAO;RIMA;
URN: URN:SI:UM:
Type (COBISS): Bachelor thesis/paper
Thesis comment: Univ. v Mariboru, Fak. za kemijo in kemijsko tehnologijo
Pages: VIII, 42 str.
ID: 10842232