In silico probir derivata kumarina i L-askorbinske kiseline na histonskoj demetilazi LSD1 - pametni dizajn novih kemoterapeutika

master's thesis

• Title (english): In silico screening of coumarin and L-ascorbic acid derivatives on histone demethylaze LSD1 - rational design of new chemotherapeutics
• Author: Rok Ister
• Mentor: Donatella Verbanac (mentor)
• Committee member: VLADIMIR TRKULJA (predsjednik povjerenstva)
• Committee member: Sanja Dolanski-Babić (član povjerenstva)
• Committee member: Donatella Verbanac (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Medical Chemistry, Biochemistry and Clinical Chemistry); Zagreb
• Defense date and country: 2018-07-13, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Medical Biochemistry

Abstract

Razvoj novih lijekova podrazumijeva dugotrajan i skup proces. Uključivanje stručnjaka iz svih područja omogućuje smanjivanje rizika od gubitka potencijalno kvalitetnih molekula tijekom tog procesa te su danas interdisciplinarni timovi imperativ za osiguravanje uspješnosti i brzine odvijanja samog tijeka istraživanja i razvoja novih terapijskih opcija. Budući da je razvoj novih
tehnologija i kompjuterskih/računskih programa omogućio relativno uspješno predviđanje ponašanja molekula u biološkim sustavima te je doprinio i ukupnom smanjenju troškova razvoja, upotreba računalne kemije danas je od velikog značaja i uvelike se koristi u farmaceutskoj industriji i u ostalim sustavima koji se bave problematikom iznalaženja novih obećavajućih molekula. U ovom radu je sa skupom novosintetiziranih hibridnih spojeva (33 kumarinsko-1,2,3-triazolna i 61 askorbinsko-1,2,3-triazolna derivata) provedeno molekularno uklapanje na poznatoj ciljnoj molekuli enzimu, LSD1 (lizin-specifičnoj demetilazi 1) kako bi se između navedenog skupa spojeva probrale aktivne molekule i pokušao pretpostaviti mehanizam njihove inhibicije ciljanog enzima koji sudjeluje u epigenetskoj regulaciji stanice. LSD1 igra vrlo važnu ulogu u modifikaciji epigenetskog izražaja stanice uklanjajući metilne skupine s lizina na histonskim podjedinicama i pojačano je izražen u neoplastičnim stanicama određenih vrsta
tumora. Model je postavljen koristeći poznate reverzibilne inhibitore LSD1 i pomoću određenih graničnih vrijednosti između aktivnih i neaktivnih spojeva probran je podskup spojeva za daljnja in vitro testiranja. Također, metodom definicije dva vezna mjesta predloženi su strukturni mehanizmi inhibicije otvarajući time mogućnost pametnog dizajniranja novih lijekova u bliskoj
budućnosti koji ciljaju na enzim LSD1 kao mjesto djelovanja.

Abstract (english)

Development of a new drug has become an expensive and long endeavor. Of the ultimate importance is acting through the multi- and inter-disciplinary teams, minimizing in this way most of the risks while selecting the most promising molecules for the further development. Computational chemistry and new technologies have enabled significant reduction of the risk of
attrition during preclinical drug development. In this work the results obtained on the set of newly synthetized hybrid compounds (33 coumarin-1,2,3-triazole and 61 L-ascorbic acid-1,2,3-triazole derivatives) on which molecular docking on the target protein has been performed, are reported. The target protein lysine-specific histone demethylase 1 (LSD1) is responsible for the epigenetic regulation within the cells. Epigenetics has been widely used in the last decade aiming also towards control of the proliferation and development of neoplastic growth. LSD1 plays an important role in modification of epigenetic behavior of the cell and as enzyme it is overexpressed in many types of malignancies. Our model was set-up utilizing known reversible inhibitors of LSD1 as comparable standards and utilizing results from the docking studies with the set of newly synthesized molecules. The results obtained are highly useful and will serve in rational drug development of further derivatives aimed to inhibit devastation activity of LSD1 as a target protein/enzyme.

• Keywords: askorbinska kiselina; in silico; kemoterapija; kumarin; lizin-specifična demetilaza 1; molekularno uklapanje; virtualni probir
• Keywords (english): ascorbic acid; chemotherapy; coumarin; in silico studies; lysine-specific demetilaze 1; molecular docking; virtual screening
• Language: croatian
• URN:NBN: urn:nbn:hr:105:700716
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2019-03-20 11:29:17