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master's thesis
Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli
Zagreb: University of Zagreb, Faculty of Science, 2018. urn:nbn:hr:217:210950
Čorak, Nina
University of Zagreb
Faculty of Science
Department of Biology

Institutional repository: Repository of the Faculty of Science

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Čorak, N. (2018). Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli (Master's thesis). Zagreb: University of Zagreb, Faculty of Science. Retrieved from https://urn.nsk.hr/urn:nbn:hr:217:210950

Čorak, Nina. "Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli." Master's thesis, University of Zagreb, Faculty of Science, 2018. https://urn.nsk.hr/urn:nbn:hr:217:210950

Čorak, Nina. "Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli." Master's thesis, University of Zagreb, Faculty of Science, 2018. https://urn.nsk.hr/urn:nbn:hr:217:210950

Čorak, N. (2018). 'Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli', Master's thesis, University of Zagreb, Faculty of Science, accessed 22 November 2024, https://urn.nsk.hr/urn:nbn:hr:217:210950

Čorak N. Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli [Master's thesis]. Zagreb: University of Zagreb, Faculty of Science; 2018 [cited 2024 November 22] Available at: https://urn.nsk.hr/urn:nbn:hr:217:210950

N. Čorak, "Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli", Master's thesis, University of Zagreb, Faculty of Science, Zagreb, 2018. Available at: https://urn.nsk.hr/urn:nbn:hr:217:210950

Metadata
TitleRačunalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli
Title (english)Computational study of interactions between azithromycin derivatives and peptidyl-transferase center of Escherichia coli ribosome
AuthorNina Čorak
MentorBranimir Bertoša (mentor)
Committee memberBranimir Bertoša (predsjednik povjerenstva)
Committee memberIvana Ivančić Baće (član povjerenstva)
Committee memberMartina Šeruga Musić (član povjerenstva)
Committee memberBiljana Balen (član povjerenstva)
GranterUniversity of Zagreb
Faculty of Science
(Department of Biology)
Zagreb
Defense date and country2018-07-03, Croatia
Scientific / art field,
discipline and subdiscipline		NATURAL SCIENCES
Biology
Abstract
U sklopu ovog diplomskog rada istražene su interakcije izmeĎu 10 različitih azitromicinskih derivata i veznog mjesta PTAR-a (engl. peptidyl transferase-associated region) velike podjedinice ribosoma bakterije Escherichia coli s ciljem dizajniranja novih, potencijalno efikasnih antibiotika. Vezanje azitromicinskih derivata u veznog mjesta PTAR-a istraženo je s pomoću računalnih metoda molekulskog uklapanja i Monte Carlo konformacijske pretrage. Prije računalnog istraživanja interakcija azitromicinskih derivata i veznog mjesta PTAR-a, konformacijski prostor svakog od 10 liganada pretražen je Monte Carlo algoritmom uz 4 različita modela otapala. Najpovoljniji konformeri pronaĎeni u svakom od modela otapala, kao i konformeri koji najbolje reprezentiraju grupe dobivene klaster analizom, korišteni su kao početne strukture prilikom istraživanja interakcija vezanja liganada u vezno mjesto PTAR-a. Rezistencijski mehanizmi patogenih bakterija otežavaju primjenu makrolidnih antibiotika u kliničkoj praksi. Jedan od najčeščih oblika rezistencije koji nalazimo kod bakterijskih patogena je dimetilacija A2058 ili A2058G supstitucija unutar 23S rRNA. Temeljem provedenog računalnog istraživanja vezanja liganada u PTAR velike podjedinice prokariotskog ribosoma utvrĎeno je da se ligand D efikasno veže u PTAR i u prisutnosti dimetiliranog A2058 što bi moglo značiti efikasnu primjenu ovog spoja i kod sojeva koji su razvili rezistenciju putem dimetiliranja A2058. Štoviše, ligand D u PTAR-u s dimetiliranim A2058 ima nižu energiju vezanja nego ligand D vezan u PTAR s A2058 koji nije metiliran. Efikasno vezanje liganda D uzrokovano je prvenstveno hidrofobnim interakcijama koje makrolaktonski prsten stvara s aminokiselinama Lys 90, Lys 91 i Arg 92, te s nukleotidom A751. Navedeni aminokiselinski i nukleotidni ogranci grade izlazni kanal PTAR-a te stoga spomenute interakcije predstavljaju potencijalno efikasni način blokiranja izlaznog kanala PTAR-a.
Abstract (english)
The aim of this graduate thesis is the designing of new, potentially effective antibiotics. Interactions between 10 different azithromycin derivatives and peptidyl-transferase center of the Escherichia coli ribosome were investigated by computational methods consisting of docking and Monte Carlo conformational searches. Prior to study of interactions between azithromycin derivatives and the PTAR binding site, the conformational space of each of the 10 ligands was investigated with Monte Carlo algorithm using 4 different solvent models. The energetically most favourable conformers of each ligand for each solvent model, as well as the cluster representatives obtained by cluster analysis, were used as starting structures for investigation of ligand binding into the PTAR binding site. Resistance mechanisms of pathogenic bacteria are a growing issue for the application of macrolide antibiotics in clinical practice. One of the most common forms of resistance found in bacterial pathogens is dimethylation A2058 and A2058G substitution within 23S rRNA. Results obtained in the frame of this thesis suggest that ligand D effectively binds to PTAR regardless of the presence of dimethylated A2058. This means that ligand D could potentially be an efficient antibiotic compound even against strains that have developed resistance to dimethylation A2058. Furthermore, ligand D, in PTAR with dimethylated A2058, has lower binding energy than ligand D bound to the PTAR with non-methylated A2058. Effective binding of ligand D is caused primarly by the hydrophobic interactions between macrolactone ring with Lys 90, Lys 91, Arg 92 and A751. Since the exit channel of PTAR consists of mentioned amino acids and nucleotides, these interactions of ligand D might represent a potentially effective way of blocking the PTAR exit channel.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:217:210950
Study programmeTitle: Molecular Biology
Study programme type: university
Study level: graduate
Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
Type of resourceText
File originBorn digital
Access conditionsOpen access
Terms of useLicence In copyright icon
Created on2018-08-29 09:58:20