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

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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)
Article number067
JournalFrontiers in Cellular and Infection Microbiology
Volume9
Issue numberMAR
DOIs
StatePublished - Jan 1 2019

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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

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, 9(MAR), [067]. https://doi.org/10.3389/fcimb.2019.00067