Virtual Screen for Repurposing of Drugs for Candidate Influenza a M2 Ion-Channel Inhibitors

Draginja Radosevic, Milan Sencanski, Vladimir Perovic, Nevena Veljkovic, Jelena Prljic, Veljko Veljkovic, Emily Mantlo, Natalya Bukreyeva, Slobodan Paessler, Sanja Glisic

Research output: Contribution to journalArticle

Abstract

Influenza A virus (IAV) matrix protein 2 (M2), an ion channel, is crucial for virus infection, and therefore, an important anti-influenza drug target. Adamantanes, also known as M2 channel blockers, are one of the two classes of Food and Drug Administration-approved anti-influenza drugs, although their use was discontinued due to prevalent drug resistance. Fast emergence of resistance to current anti-influenza drugs have raised an urgent need for developing new anti-influenza drugs against resistant forms of circulating viruses. Here we propose a simple theoretical criterion for fast virtual screening of molecular libraries for candidate anti-influenza ion channel inhibitors both for wild type and adamantane-resistant influenza A viruses. After in silico screening of drug space using the EIIP/AQVN filter and further filtering of drugs by ligand based virtual screening and molecular docking we propose the best candidate drugs as potential dual inhibitors of wild type and adamantane-resistant influenza A viruses. Finally, guanethidine, the best ranked drug selected from ligand-based virtual screening, was experimentally tested. The experimental results show measurable anti-influenza activity of guanethidine in cell culture.

Original languageEnglish (US)
Number of pages1
JournalFrontiers in Cellular and Infection Microbiology
Volume9
DOIs
StatePublished - Jan 1 2019

Fingerprint

Drug Repositioning
Ion Channels
Human Influenza
Adamantane
Pharmaceutical Preparations
Guanethidine
Influenza A virus
Ligands
Preclinical Drug Evaluations
Virus Diseases
United States Food and Drug Administration
influenza A virus M2 protein
Drug Resistance
Computer Simulation
Cell Culture Techniques
Viruses

Keywords

  • drug repurposing
  • drug resistance
  • IAV matrix protein 2
  • influenza A
  • virtual screening

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Virtual Screen for Repurposing of Drugs for Candidate Influenza a M2 Ion-Channel Inhibitors. / Radosevic, Draginja; Sencanski, Milan; Perovic, Vladimir; Veljkovic, Nevena; Prljic, Jelena; Veljkovic, Veljko; Mantlo, Emily; Bukreyeva, Natalya; Paessler, Slobodan; Glisic, Sanja.

In: Frontiers in Cellular and Infection Microbiology, Vol. 9, 01.01.2019.

Research output: Contribution to journalArticle

Radosevic, D, Sencanski, M, Perovic, V, Veljkovic, N, Prljic, J, Veljkovic, V, Mantlo, E, Bukreyeva, N, Paessler, S & Glisic, S 2019, 'Virtual Screen for Repurposing of Drugs for Candidate Influenza a M2 Ion-Channel Inhibitors', Frontiers in Cellular and Infection Microbiology, vol. 9. https://doi.org/10.3389/fcimb.2019.00067
Radosevic, Draginja ; Sencanski, Milan ; Perovic, Vladimir ; Veljkovic, Nevena ; Prljic, Jelena ; Veljkovic, Veljko ; Mantlo, Emily ; Bukreyeva, Natalya ; Paessler, Slobodan ; Glisic, Sanja. / Virtual Screen for Repurposing of Drugs for Candidate Influenza a M2 Ion-Channel Inhibitors. In: Frontiers in Cellular and Infection Microbiology. 2019 ; Vol. 9.
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