Načrtovanje in razvoj novih protimikrobnih spojin z uporabo ProBiS računalniških pristopov

Kores, Katarina

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Title:	Načrtovanje in razvoj novih protimikrobnih spojin z uporabo ProBiS računalniških pristopov
Authors:	ID Kores, Katarina (Author) ID Bren, Urban (Mentor) More about this mentor... ID Konc, Janez (Comentor)
Files:	MAG_Kores_Katarina_2018.pdf (2,17 MB) MD5: 1841473650AD8AE0E692B5BD9111D299 PID: 20.500.12556/dkum/2ca0dcae-7b02-46c1-a5ba-d1e893f1e852
Language:	Slovenian
Work type:	Master's thesis/paper
Typology:	2.09 - Master's Thesis
Organization:	FKKT - Faculty of Chemistry and Chemical Engineering
Abstract:	Mikroorganizmi, kamor uvrščamo bakterije, glive in viruse, še danes povzročajo veliko bolezni, učinkovitost zdravil pa zaradi večanja odpornosti mikroorganizmov upada. Zato je iskanje novih protimikrobnih spojin izredno pomembno. V magistrski nalogi smo se osredotočili na encim metionin aminopeptidazo, katerega naloga je pospeševanje odstranjevanja N-terminalnega metionina v procesu translacije. Njegova inhibicija bi namreč lahko predstavljala zametke zdravljenja raka in bakterijskih infekcij, saj se encim v različnih tipih nahaja v več mikroorganizmih; mi smo osredotočili na bakteriji Escherichia coli in Mycobacterium tuberculosis. Encim metionin aminopeptidaza v vezavnem mestu vsebuje dva kovinska iona. Posledično smo se osredotočili na iskanje novih potencialnih protimikrobnih spojin, ki imajo sposobnost keliranja. Keliranje oziroma kelacijski efekt predstavlja koordinativno vezavo liganda na kovinski atom z vsaj dvema koordinacijskima vezema, pri procesu kelacije pa se ustvari 5- ali 6-členski obroč. Problema smo se lotili s pomočjo računalniškega modeliranja, ki se vedno pogosteje uporablja pri razvoju novih zdravil. Nove protimikrobne spojine smo iskali s tehniko molekulskega sidranja, ki smo ga izvajali z računalniškim programom, ki ga razvijajo v Laboratoriju za molekularno modeliranje na Kemijskem inštitutu. Iz podatkovne baze ZINC smo pripravili bazo ligandov, sposobnih kelacije, z večstopenjskim filtriranjem malih molekul glede na njihove SMARTS opise. Prav tako smo pripravili proteinske strukture metionin aminopeptidaze za oba organizma in koordinate vezavnih mest. Pridobili smo 19 novih spojin, ki so kazale velik potencial za inhibicijo encima na osnovi kelatnega efekta.
Keywords:	protimikrobne spojine, metinonin aminopeptidaza, kelatni efekt, ProBiS, molekulsko sidranje
Place of publishing:	Maribor
Publisher:	[K. Kores]
Year of publishing:	2018
PID:	20.500.12556/DKUM-72703
UDC:	604.4:615.33(043.2)
COBISS.SI-ID:	21924886
NUK URN:	URN:SI:UM:DK:IMOROHHD
Publication date in DKUM:	04.12.2018
Views:	1492
Downloads:	148
Metadata:
Categories:	KTFMB - FKKT
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Licences

License:	CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International

Link:	http://creativecommons.org/licenses/by-nc-nd/4.0/
Description:	The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Licensing start date:	17.10.2018

Secondary language

Language:	English
Title:	Design and development of new antimicrobial compounds using ProBiS computational approaches
Abstract:	Microorganisms, which consist of bacteria, fungi in viruses, still cause many diseases, and the effectiveness of current medicines is reduced due to the increased resistance of microorganisms. Therefore, finding new antimicrobial compounds is of utmost importance. In this master thesis, we focused on enzyme methionine aminopeptidase, whose task is to accelerate the removal of N-terminal methionine in the translation process. Its inhibition might represent a way for cancer and bacterial infections treatment, since methionine aminopeptidase can be found in different types and in several microorganisms; we focused on Escherichia coli in Mycobacterium tuberculosis. The enzyme methionine aminopeptidase contains two metal ions in its binding site. Therefore, we focused on finding new potential antimicrobial compounds that have the ability to chelate. The chelating or chelating effect is a coordinative binding of the ligand to a metal atom with at least two coordinative bonds, and during this process a 5- or 6-membered ring is formed. The problem was addressed by computer modeling, which is being increasingly used in the development of new drugs. We were looking for new antimicrobial compounds using the molecular docking technique, which we performed by a computer program developed within the Laboratory for Molecular Modeling at the National Institute of Chemistry. From the ZINC database, we prepared a subset of ligands capable of chelation using several stepwise filters of small molecules with respect to their SMARTS descriptors. We also prepared protein structures of methionine aminopeptidase for both organisms as well as their binding site coordinates. We obtained 19 new compounds that showed great potential for enzyme inhibition based on chelating effects.
Keywords:	antimicrobial agents, methionine aminopeptidase, chelate effect, ProBiS, molecular docking

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