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Molecular dynamics simulations and computational design of inhibitors of protein lysine methyltransferase EZH2

dc.contributor.advisorErić, Slavica
dc.contributor.otherSavić, Vladimir
dc.contributor.otherZloh, Mire
dc.creatorKalinić, Marko D.
dc.date.accessioned2020-07-03T09:47:47Z
dc.date.available2020-07-03T09:47:47Z
dc.date.issued2015-12-17
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=2357
dc.identifier.urihttps://nardus.mpn.gov.rs/handle/123456789/4242
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:10309/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=47502607
dc.description.abstractEnhancer of Zeste Homolog 2 (EZH2) je epigenetski enzim koji vrši selektivno metilovanje lizina 27 na histonu H3 (H3K27). Trimetilovani H3K27 je represivan epigenetski signal, cime EZH2 utice na smanjenje transkripcije ciljnih gena. Prekomerna aktivnost EZH2, izazvana povecanom ekspresijom ili mutacijama njegovog katalitickog domena, dovedena je u vezu sa vecim brojem maligniteta kod ljudi, a inhibicija ovog enzima smatra se perspektivnom strategijom u razvoju novih antitumorskih lekova. Prvi selektivni inhibitori EZH2 otkriveni su 2012. godine i njihova biološka karakterizacija potvrdila je terapijski potencijal inhibicije ovog epigenetskog regulatora. Iako postoji potreba za otkricem novih inhibitora, znacajnu prepreku u njihovom dizajnu do sada je predstavljao nedostatak trodimenzionalne strukture kompleksa EZH2 i okarakterisanih liganada. Cilj istraživanja u okviru ove doktorske disertacije bio je da se primenom racunarskih metoda uspostavi i validira model vezivnog mesta EZH2, i da se, zatim, uspostavljeni model upotrebi u dizajnu novih inhibitora kao potencijalnih antitumorskih lekova. U prvoj fazi istraživanja izvršeno je homologo modeliranje katalitickog domena EZH2 koji sadrži vezivno mesto za kofaktor, a za koje se kompetitivno vezuju svi poznati inhibitori. Pocetni model usavršen je primenom simulacija konvencionalne i ubrzane molekularne dinamike (MD), a zatim je daljim simulacijama istraživano kako 13 inhibitora piridonske strukture stupa u interakciju sa vezivnim mestom na enzimu. Korišcenjem prikupljenih trajektorija izvršena je procena slobodne energije vezivanja inhibitora zasnovana na molekularnoj mehanici uz generalizovani Bornov model rastvaraca (MM/GBSA). Izracunate energije upore ene su sa dostupnim eksperimentalnim podacima i utvr eno je dobro slaganje izme u vrednosti koje ukazuje na validnost uspostavljenog modela. Daljom analizom trajektorija i primenom racunarske mutageneze u alanin identifikovane su intermolekulske interakcije koje kljucno doprinose aktivnosti i selektivnosti proucavanih inhibitora. Na ovim osnovama, definisan je farmakoforni model inhibitora EZH2 a njegovom validacijom potvr ena je mogucnost uspešne identifikacije i inhibitora baziranih na drugim osnovnim strukturama. Efikasnost mnogih antitumorskih lekova ogranicava razvoj rezistencije tui morskih celija, pri cemu je opisan veci broj mehanizama koji dovode do pojave rezistencije...en
dc.description.abstractmethylation of lysine 27 on histone H3. Trimethylated H3K27 constitutes a repressive epigenetic mark, making EZH2 capable of transcriptional silencing of target genes. Aberrant EZH2 activity, caused by either overexpression or point mutations in the catalytic domain, has been related to a number of human malignancies, making EZH2 inhibition a promising strategy in the development of novel anticancer treatments. First disclosure of selective EZH2 inhibitors in 2012 and their biological characterization has confirmed the therapeutic potential of inhibiting this epigenetic regulator. While there is an outstanding need for the discovery of novel EZH2 inhibitors, the lack of a three-dimensional structure of EZH2 complexed with one of its ligands has been a significant obstacle to this end. The aim of research conducted as part of this doctoral dissertation was to establish and validate a model of EZH2 binding site using computational methods, and to subsequently utilize the established model as a foundation in the design of novel potential EZH2 inhibitors. In the first stage of our research, homology modeling of the EZH2 catalytic domain was conducted, which contains the cofactor binding site targeted by all known inhibitors. The initial model was refined through conventional and accelerated molecular dynamics (MD) simulations. Next, structures of EZH2 complexed with 13 different pyridone inhibitors were simulated in order to study the key interactions participating in ligand binding. An assessment of inhibitors’ binding free energy was performed using the molecular mechanics/generalized Born surface area (MM/GBSA) method. The computed energies were correlated to available experimental data and good agreement was found supporting the validity of the established model. Further analysis of MD trajectories and computational alanine scanning facilitated the definition of key intermolecular interactions that contribute to the observed potency and selectivity of the studied inhibitors. On this basis, a pharmacophore model of EZH2 inhibitors was proposed and validated. It demonstrated good capabilities in identifying truly active molecules, including those not based on a pyridone scaffold, in presence of decoys. The efficacy of anticancer drugs can become limited with the onset of resiiv stance that can develop in cancer cells through various mechanisms...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Фармацеутски факултетsr
dc.rightsopenAccessen
dc.rights.urihttps://creativecommons.org/licenses/by-sa/4.0/
dc.sourceУниверзитет у Београдуsr
dc.subjectEnhancer of Zeste Homolog 2sr
dc.subjectEnhancer of Zeste Homolog 2en
dc.subjectepigeneticsen
dc.subjectanticancer drugsen
dc.subjectmolecular dynamicsen
dc.subjectde novo designen
dc.subjectP-glycoproteinen
dc.subjectbreast cancer resistance proteinen
dc.subjectBCRPen
dc.subjectcomputational classification modelsen
dc.subjectepigenetikasr
dc.subjectantitumorski lekovisr
dc.subjectmolekularna dinamikasr
dc.subjectde novo dizajnsr
dc.subjectP-glikoproteinsr
dc.subjectprotein rezistencije karcinoma dojkesr
dc.subjectBCRPsr
dc.subjectklasifikacioni racunarski modelisr
dc.titleSimulacije milekularne dinamike i računarsko dizajniranje inhibitora protein lizin metiltransferaze EZH2sr
dc.titleMolecular dynamics simulations and computational design of inhibitors of protein lysine methyltransferase EZH2en
dc.typedoctoralThesisen
dc.rights.licenseBY-SA
dcterms.abstractЕрић, Славица; Савић, Владимир; Злох, Мире; Калинић, Марко Д.; Симулације милекуларне динамике и рачунарско дизајнирање инхибитора протеин лизин метилтрансферазе ЕЗХ2; Симулације милекуларне динамике и рачунарско дизајнирање инхибитора протеин лизин метилтрансферазе ЕЗХ2;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24278/Disertacija115.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24279/Marko_Kalinic_referat_FF.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/24278/Disertacija115.pdf
dc.identifier.fulltexthttps://nardus.mpn.gov.rs/bitstream/id/24279/Marko_Kalinic_referat_FF.pdf
dc.identifier.rcubhttps://hdl.handle.net/21.15107/rcub_nardus_4242


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