Konformacijska pretraga strukturnih derivata azitromicina i njihovo molekulsko uklapanje u peptidil-transferazni centar velike podjedinice ribosoma bakterije Escherichia coli

master's thesis

• Title (english): Conformational search of azithromycin structural derivatives and their docking into peptidyl- transferase center of Escherichia coli large ribosomal subunit
• Author: Sonja Škevin
• 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: Nenad Malenica (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2020-06-16, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Makrolidni antibiotici u širokoj su upotrebi od pedesetih godina dvadesetog stoljeća. Tijekom njihove dugogodišnje upotrebe u medicini i veterini došlo je do pojave rezistencije. Cilj ovog diplomskog rada bio je istražiti vezanje deset strukturnih derivata azitromicina u regiju PTAR ribosoma bakterije Escherichia coli metodom molekulskog uklapanja. Prvi korak bio je pretražiti konformacijski prostor svakog liganda metodom Monte Carlo uz korištenje četiri različita modela otapala. Najzastupljeniji konformeri korišteni su kao početne strukture u računima molekulskog uklapanja u regiju PTAR bakterijskog ribosoma. Računima molekulskog uklapanja izračunat je afinitet svih deset liganada za vezanje u vezno mjesto PTAR bakterijskog ribosoma. S obzirom da se rezistencija na makrolide temelji na dimetilaciji A2058 ili A2058G supstituciji, pronađen je ligand s najvećim potencijalom za aktivnost protiv bakterija rezistentnih na makrolide. Kod tog liganda, pet pronađenih energijski najpovoljnijih načina vezanja ne ostvaruje interakcije s A2058. Analiza rezultata računa molekulskog uklapanja za svih deset liganada ukazala je na važnost π-π interakcija za stabilizaciju liganda u veznom mjestu. Predložena su tri nova liganda kod kojih bi potencijal za ostvarivanje π-π interakcija u veznom mjestu PTAR ribosoma bakterije Escherichia coli trebao biti još izraženiji.

Abstract (english)

Macrolides are widely used antibiotics since 1950s. Their extensive use in medicine and veterinary medicine has led to the development of resistance. Goal of this thesis is to study binding of ten structural derivatives of azitromycin to PTAR region of Escherichia coli ribosome using computational methods, primarily docking. First step was to conduct Monte Carlo conformational searches of all ten ligands using four different solvent models. The representative conformers were used as input structures for docking study of their binding into bacterial PTAR. Binding affinities of all ten ligands into E. coli PTAR were obtained. Ligand that does not interact with A2058 within its five best binding modes was identified. That ligand is considered as the one with the greatest potential of effectiveness against macrolide resistant bacteria since bacterial resistance to macrolides is based on A2058 dimethylation or A2058G substitution. Analysis of the results obtained by docking pointed to the importance of π-π interactions for ligand stabilisation within bacterial PTAR. Three ligands with enhanced potential for π-π interactions within Escherichia coli PTAR are proposed proposal for further research

• Keywords: makrolidi; računalna biologija; konformacijska pretraga Monte Carlo; molekulsko uklapanje
• Keywords (english): macrolides; computational biology; Monte Carlo conformational search; molecular docking
• Language: croatian
• URN:NBN: urn:nbn:hr:217:085885
• 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: 2020-07-13 06:31:13