Računalno istraživanje vezanja strukturnih derivata azitromicina u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli

master's thesis

• Title (english): Computational study of interactions between azithromycin derivatives and peptidyl-transferase center of Escherichia coli ribosome
• Author: Nina Čorak
• Mentor: Branimir Bertoša (mentor)
• Committee member: Branimir Bertoša (predsjednik povjerenstva)
• Committee member: Ivana Ivančić Baće (član povjerenstva)
• Committee member: Martina Šeruga Musić (član povjerenstva)
• Committee member: Biljana Balen (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2018-07-03, 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: rezistentni bakterijski sojevi; makrolidi; molekulsko uklapanje; Monte Carlo konformacijska analiza
• Keywords (english): antibiotic resistant bacteria; macrolides; molecular docking; Monte Carlo conformational search
• Language: croatian
• URN:NBN: urn:nbn:hr:217:210950
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2018-08-29 09:58:20