Title (srp)

In silico odabir lekova iz baze DrugBank kao potencijalnih inhibitora M2 proteina virusa gripa i provera njihove aktivnosti in vitro : doktorska disertacija

Author

Radošević, Draginja, 1986-

Contributor

Glišić, Sanja, molekularni biolog
Brajušković, Goran, 1985-
Senćanski, Milan V.
Glišić, Sanja, molekularni biolog
Brajušković, Goran, 1985-

Description (eng)

The influenza virus is permanent global health threat with epidemic and pandemic potential. Inaddition to vaccination, which is the first line of defense against influenza, antivirals play an essentialrole in prevention and therapy during epidemics and pandemics. Due to the suboptimal effectivenessof vaccination and limitations of current antiviral therapies because of drug resistance and theemergence of new circulating viral strains, novel effective anti-influenza drugs are urgently needed.Influenza A virus (IAV) matrix protein 2 (M2), an ion channel, is crucial for virus infection, andtherefore, an important anti-influenza drug target. Adamantanes, also known as M2 channel blockers,were the first approved Food and Drug Administration class- anti-influenza drugs, although their usewas discontinued due to prevalent drug resistance.This study identified and proposed a simple bioinformatics criterion for virtual screening ofmolecular libraries for potential dual inhibitors of influenza A M2 ion channel for both wild type(WT) and amantadine resistant viruses.Results of this study are founded on a simple theoretical criterion for virtual screening of molecularlibraries based on the long-range interactions characterized by the molecular descriptors — theaverage quasi valence number (AQVN) and the electron-ion interaction potential (EIIP). The data onknown M2 inhibitors were collected and analyzed for influenza A M2 protein inhibitors both for WTinfluenza A viruses and their amantadine-resistant mutants. Based on the results of this analysis, theEIIP/AQVN criterion for the selection of drugs candidates from the databases that could representdual inhibitors of both influenza virus M2 WT protein and M2 S31N mutant was established.By applying the EIIP/AQVN-based virtual screening criterion, 39 drugs were selected out of 2,627approved drugs from the DrugBank as potential dual influenza M2 ion channel inhibitors.Further, the data collected on known M2 protein inhibitors were used to establish a chemoinformaticcriterion for M2 protein (VS) based on the mutual structural similarity of molecules (ligand-basedVS) and structural compatibility of inter-reactive molecules and corresponding binding energies(molecular docking).After in silico screening of drug space using the EIIP/AQVN filter and further filtering of drugs byligand-based virtual screening, the best five candidates from DrugBank were proposed. Further,molecular docking of five selected candidates to both the wild-type M2 channel and S31N mutantchannel, was performed. The candidate with the lowest binding energy and equal affinity to both theWT channel and S31N mutant channel was the anticholinergic drug cycrimine. The experimentalresults showed the anti-influenza activity of cycrimine against two different influenzas A subtypes2009 H1N1 pandemic influenza and H3N2. As the best-ranked drug selected from ligand-basedvirtual screening, guanethidine showed measurable anti-influenza activity against the 2009 H1N1pandemic influenza virus in cell culture.Our work has shown that the proposed in silico criterion represents an useful tool for selection ofcandidate M2 inhibitors of influenza viruses type A by screening of the approved drugs and othermolecular libraries.

Description (srp)

Virus influence tipa A zbog svog značajnog epidemijskog i pandemijskog potencijala predstavljatrajnu globalnu pretnju za zdravlje ljudi. Pored vakcinacije koja predstavlja prvu liniju odbrane protivgripa, antivirusni lekovi imaju važnu ulogu u prevenciji i terapiji tokom epidemija i pandemija Zbognedovoljne efikasnosti vakcina protiv sezonskog gripa, kao i neodgovarajuće antivirusne terapije,koji su uslovljeni pojavom rezistencije na postojeće lekove i pojavom novih sojeva virusa, hitno supotrebni novi efikasni lekovi protiv gripa. Protein M2 virusa influence A (M2) je jonski kanal koji jeneophodan za virusnu infekciju, i zbog toga je važna terapeutska meta gripa. Adamantani, inhibitoriM2 jonskog kanala influence su bili prvi lekovi koje je FDA odobrio protiv gripa, mada je njihovaupotreba obustavljena zbog rezistencije virusa na ovu klasu lekova.Osnovni cilj ove teze je identifikacija i predlaganje jednostavnog teorijskog kriterijuma za virtuelnopretraživanje molekulskih biblioteka za potencijalne dualne inhibitore M2 jonskog kanala kod virusainfluence tipa A, divljih vrsta (WT) i virusa rezistentnih na amantadin. Rezultati ove studije zasnivajuse na primeni bioinformatičkog EIIP/AQVN kriterijuma za virtuelno pretraživanje molekulskihbiblioteka zasnovanog na analizi dugodosežnih međumolekulskih interakcija.Podaci o poznatim M2 inhibitorima su prikupljeni i analizirani kako za inhibitore M2 proteinainfluence tip A, divljeg tipa, tako i za inhibitore M2 mutanta S31N. Na osnovu ove analize određenje bioinformatički kriterijum zasnovan na EIIP/AQVN parametrima za virtuelno pretraživanjemolekulskih biblioteka u cilju identifikacije kandidata za dvostruke inhibitora M2 jonskog kanalaWT influence A virusa i virusa sa mutacijom S31N u proteinu M2. Na osnovu primene ovogkriterijuma za virtuelni skrining odabrano je 39 lekova od 2627 lekova iz baze DrugBank.Posle primene hemoinformatičkog kriterijuma za virtuelni skrining (VS) koji se zasniva nameđusobnoj strukturnoj sličnosti (ligand zasnovani VS) poznatih inhibitora M2 proteina sakandidatima za lekove - dvostruke inhibitora M2 jonskog kanala WT influence A virusa i virusa samutacijom S31N u proteinu M2 od 39 lekova je predoženo pet najboljih kandidata, a kao najboljimeđu njima je gvanetidin. Molekuskim dokingom pet kandidata na divlji tip M2 i mutirani M1 S31Nkao kandidat sa najmanjom energijom vezivanja i jednakim afinitetom za oba kanala je identifikivanlek cikrimin.Rezultati eksperimenta in vitro su potvrdili predloženu aktivnost cikrimina protiv dva različitapodtipa virusa influence A pandemijskog H1N1 2009 i H3N2, a takođe je utvrđena in vitro aktivnostgvanetidina protiv pandemijskog virusa influence H1N1 2009.Predloženi bioinformatički kriterijum predstavlja osnov za selekciju dvostrukih inhibitora M2jonskih kanala WT influence A virusa i virusa sa mutacijom S31N u proteinu M2 iz bilo kojemolekulske biblioteke malih molekula.

Description (srp)

Molekularna biologija - Molecular biology / Bioinformatics - Bioinformatika Datum odbrane: 11.10.2021.

Object languages

Serbian

Date

2021

Rights

© All rights reserved

Subject

OSNO - Opšta sistematizacija naučnih oblasti, Molekularna biologija

Influenza A virus, M2 protein, virtual screening, EIIP/AQVN, drug repurposing

Identifiers