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master's thesis
Dizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala
2020. urn:nbn:hr:193:804412
Grizelj, Paulina
University of Rijeka
Faculty of Biotechnology and Drug Development

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Grizelj, P. (2020). Dizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala (Master's thesis). Rijeka: University of Rijeka. Retrieved from https://urn.nsk.hr/urn:nbn:hr:193:804412

Grizelj, Paulina. "Dizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala." Master's thesis, University of Rijeka, 2020. https://urn.nsk.hr/urn:nbn:hr:193:804412

Grizelj, Paulina. "Dizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala." Master's thesis, University of Rijeka, 2020. https://urn.nsk.hr/urn:nbn:hr:193:804412

Grizelj, P. (2020). 'Dizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala', Master's thesis, University of Rijeka, accessed 28 December 2024, https://urn.nsk.hr/urn:nbn:hr:193:804412

Grizelj P. Dizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala [Master's thesis]. Rijeka: University of Rijeka; 2020 [cited 2024 December 28] Available at: https://urn.nsk.hr/urn:nbn:hr:193:804412

P. Grizelj, "Dizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala", Master's thesis, University of Rijeka, Rijeka, 2020. Available at: https://urn.nsk.hr/urn:nbn:hr:193:804412

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Metadata
TitleDizajn inhibitora ubikvitin tioesteraze OTUB1 pomoću superračunala
Title (english)Structure-based design of novel ubiquitin thioesterase OTUB1 inhibitors using supercomputer
AuthorPaulina Grizelj
MentorŽeljko Svedružić (mentor)
Committee memberMiranda Mladinić Pejatović (predsjednik povjerenstva)
Committee memberKarlo Wittine (član povjerenstva)
GranterUniversity of Rijeka
(Faculty of Biotechnology and Drug Development)
Rijeka
Defense date and country2020-09-17, Croatia
Scientific / art field,
discipline and subdiscipline		BIOTECHNICAL SCIENCES
Biotechnology
Bioinformatics
Abstract
Značaj: Ubikvitinacija je modifikacija u kojoj se na protein kovalentno veže ubikvitin (Ub). Deubikvitinacija je reverzibilni proces ubikvitinaciji, modifikacija u kojoj se uklanja ubikvitin sa proteina. Ravnoteža tih dvaju procesa održava razinu i aktivnost proteina u stanici, a njihova disfunkcija dovodi do nastanka različitih patoloških stanja. Deubikvitinaciju u stanici provode deubikvitinirajući enzimi, kao što je protein ubikvitin tioesteraza OTUB1. Ubikvitin tioesteraza regulira aktivnost proteina p53 i ubikvitinaciju RAS proteina. Zbog povezanosti sa proteinima koji sudjeluju u nastanku tumora, inhibicija ubikvitin tioesteraze u stanici bi mogla biti potencijalna meta u razvoju protutumorskih lijekova. Rezultati: Virtualnim probirom pronalaze se spojevi koji su komercijalno dostupni. Odabrani spojevi mogu kompetitivno inhibirati ubikvitin tioesterazu zbog svoje strukture i načina vezanja na vezno mjesto ubikvitina na proteinu. Vezno mjesto ubikvitina na proteinu ima aminokiselinske ostatke fenilalanina. Poželjno je da spoj kandidat ima aromatske prstene u strukturi, da bi se na protein mogao vezati π-π stacking interakcijama. Simulacijama molekularne dinamike prikazuje se inhibicija proteina ubikvitin tioesteraze. Koliko je dobra inhibicija proteina ovisi o interakcijama između spojeva i veznog mjesta na proteinu. Računalnim metodama određuju se ADME svojstva spojeva kandidata te pronalaze strukture slične biološke aktivnosti (bioizosteri). Zaključak: Određeni komercijalno dostupni spojevi mogu inhibirati deubikvitinirajući enzim ubikvitin tioesterazu OTUB1. Inhibitori ubikvitin tioesteraze mogli bi se koristiti kao protutumorski lijekovi. Molekularna dinamika može se koristiti za razvoj takvih kandidata za lijekove.
Abstract (english)
Background: Ubiquitination modifies proteins by covalent attachment of ubiquitin (Ub). Deubiquitination, the reversible process of ubiquitination, removes ubiquitin from the proteins. Balance between these two processes regulates cellular protein levels and activity. Disfunction of ubiquitination and deubiquitination leads to development of pathological conditions in the cell. Deubiquitinases are enzymes that carry out protein deubiquitination. Deubiquitinase ubiquitin thioesterase OTUB1 regulates activity of p53 protein and RAS protein ubiquitination. Cellular inhibition of ubiquitin thioesterase could be a potential target in development of antitumour agents. Results: Virtual screening of comercially available compounds can be performed using computer aided drug design. Some compounds can competitively inhibit ubiquitin thioesterase OTUB1. Ubiquitin binding site on protein OTUB1 has phenylalanine residues. Therefore, it is preferable that compound has an aromatic ring in its structure. That way it can bind on ubiquitin binding site with π-π stacking interactions. Molecular dynamics simulations show ubiquitin thioesterase inhibition. Interactions between drug candidates and binding site determine how good is the protein inhibition. ADME properties can be defined using computer methods, as well as the chemical compounds with similar structures (bioisosteres). Conclusion: Certain commercially available compounds can inhibit deubiquitinase ubiquitin thioesterase OTUB1. Inhibitors of ubiquitin thioesterase could be used as antitumour agents. Molecular dynamics can be used to develop such drug candidates.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:193:804412
Study programmeTitle: Drug research and development
Study programme type: university
Study level: graduate
Academic / professional title: magistar/magistra istraživanja i razvoja lijekova (magistar/magistra istraživanja i razvoja lijekova)
Type of resourceText
File originBorn digital
Access conditionsOpen access
Terms of useLicence In copyright icon
Created on2020-09-14 19:02:19