Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2

Jun Wang, Chunlong Ma, Giacomo Fiorin, Vincenzo Carnevale, Tuo Wang, Fanghao Hu, Robert A. Lamb, Lawrence H. Pinto, Mei Hong, Michael L. Klein, William F. Degrado

Research output: Contribution to journalArticlepeer-review


Influenza A virus M2 (A/M2) forms a homotetrameric proton selective channel in the viral membrane. It has been the drug target of antiviral drugs such as amantadine and rimantadine. However, most of the current virulent influenza A viruses carry drug-resistant mutations alongside the drug binding site, such as S31N, V27A, and L26F, etc., each of which might be dominant in a given flu season. Among these mutations, the V27A mutation was prevalent among transmissible viruses under drug selection pressure. Until now, V27A has not been successfully targeted by small molecule inhibitors, despite years of extensive medicinal chemistry research efforts and high throughput screening. Guided by molecular dynamics (MD) simulation of drug binding and the influence of drug binding on the dynamics of A/M2 from earlier experimental studies, we designed a series of potent spirane amine inhibitors targeting not only WT, but also both A/M2-27A and L26F mutants with IC 50s similar to that seen for amantadine's inhibition of the WT channel. The potencies of these inhibitors were further demonstrated in experimental binding and plaque reduction assays. These results demonstrate the power of MD simulations to probe the mechanism of drug binding as well as the ability to guide design of inhibitors of targets that had previously appeared to be undruggable.

Original languageAmerican English
Pages (from-to)12834-12841
Number of pages8
JournalJournal of the American Chemical Society
Issue number32
StatePublished - Aug 17 2011
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

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