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Retrosintezno zasnovana in silico optimizacija protivirusnih učinkovin z delovanjem na 3C in 3CL proteaze = Retrosynthesis-driven in silico optimization of antiviral agents targeting 3C and 3C-like proteases : univerzitetni študijski program II. stopnje industrijska farmacijaBreznik, Marko, 1994-Obstaja nujna potreba po razvoju novih rešitev za zdravljenje virusnih bolezni brez komercialno dostopnih zdravil. Raziskave protivirusnih učinkovin ostajajo ključnega pomena in ponujajo osnovo za ... spopadanje z izbruhi virusnih bolezni v prihodnosti, tveganje katerih se ne sme ponovno zanemariti. 3C proteaza (3Cpro) ter funkcionalno in strukturno podobna 3C podobna proteaza (3CLpro) igrata ključno vlogo pri virusni replikaciji in imata izrazito ohranjeno aktivno mesto med različnimi vrstami virusov, zaradi česar sta odlični tarči za zdravljenje pikornavirusnih, kalicivirusnih in/ali koronavirusnih okužb. V tej nalogi opisujemo retrosintezno voden pristop k optimizaciji spojine MLC3 - novega tipa inhibitorja 3Cpro Enterovirusa 68, ki z encimom tvori Meisenheimerjev kompleks. MLC3 domnevno zaseda samo S1 žepek aktivnega mesta. Ker je struktura S1 žepka ena glavnih skupnih značilnosti 3Cpro in 3CLpro, smo po enterovirusno usmerjeni optimizaciji in silico ovrednotili potencial širokospektralnega protivirusnega delovanja izbranih derivatov MLC3. Naš pristop k optimizaciji je bil sestavljen iz dveh metod. Prva metoda je >>rast fragmenta<< - dodajanje substituentov, ki tvorijo dodatne interakcije z aktivnim mestom, hkrati pa ohranjajo že obstoječe interakcije MLC3 ogrodja. Z retrosintezo smo prepoznali komercialno dostopne primarne reaktante za sintezo derivatov in z uporabo analitične platforme ustvarili virtualno knjižnico z 153.675 derivati spojine MLC3. Predstavljamo dve hipotezi o vezavi MLC3 in na njuni podlagi dva farmakoforja, tvorjena z namenom virtualnega rešetanja MLC3 derivatov. Rezultati virtualnega rešetanja so bili sidrani v aktivno mesto 3Cpro. Vsako spojino smo nato ocenili glede na prileganje značilnostim izvirne farmakoforne poizvedbe. Izrazito ugodne interakcije z encimom smo prepoznali pri devetnajstih derivatih, ki so predstavljeni v nalogi. Druga metoda optimizacije je analiza razmerja med strukturno in aktivnostjo >>ogrodja<< - MLC3. V katalogih komercialno dostopnih spojin smo odkrili trinajst strukturnih analogov MLC3, ki so navedeni za nadaljnje in vitro preskuse.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [M. Breznik], 2021Language - englishCOBISS.SI-ID - 55880195
Author
Breznik, Marko, 1994-
Other authors
Gobec, Stanislav, 1970- |
Wolber, Gerhard
Topics
Zdravilne učinkovine |
Virusne bolezni |
načrtovanje učinkovin |
hit to lead |
pikornavirus |
enterovirus |
inhibitor
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Library/institution |
City | Acronym | For loan | Other holdings |
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Breznik, Marko, 1994- | ![]() |
Gobec, Stanislav, 1970- | 15284 |
Wolber, Gerhard | ![]() |
Source: Personal bibliographies
and: SICRIS
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