Designing Inhibitors of M2 Proton Channel against H1N1 Swine Influenza Virus

Anil Kumar Tyagi,Ri-Bo Huang,Kuo-Chen Chou,Shu-Qing Wang,Qi-Shi Du

doi:10.1371/journal.pone.0009388

Anil Kumar Tyagi, Ri-Bo Huang + Show 3 more

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https://doi.org/10.1371/journal.pone.0009388

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Abstract

BackgroundM2 proton channel of H1N1 influenza A virus is the target protein of anti-flu drugs amantadine and rimantadine. However, the two once powerful adamantane-based drugs lost their 90% bioactivity because of mutations of virus in recent twenty years. The NMR structure of the M2 channel protein determined by Schnell and Chou (Nature, 2008, 451, 591–595) may help people to solve the drug-resistant problem and develop more powerful new drugs against H1N1 influenza virus.MethodologyDocking calculation is performed to build the complex structure between receptor M2 proton channel and ligands, including existing drugs amantadine and rimantadine, and two newly designed inhibitors. The computer-aided drug design methods are used to calculate the binding free energies, with the computational biology techniques to analyze the interactions between M2 proton channel and adamantine-based inhibitors.Conclusions1) The NMR structure of M2 proton channel provides a reliable structural basis for rational drug design against influenza virus. 2) The channel gating mechanism and the inhibiting mechanism of M2 proton channel, revealed by the NMR structure of M2 proton channel, provides the new ideas for channel inhibitor design. 3) The newly designed adamantane-based inhibitors based on the modeled structure of H1N1-M2 proton channel have two pharmacophore groups, which act like a “barrel hoop”, holding two adjacent helices of the H1N1-M2 tetramer through the two pharmacophore groups outside the channel. 4) The inhibitors with such binding mechanism may overcome the drug resistance problem of influenza A virus to the adamantane-based drugs.

Highlights

The outbreak of H1N1 influenza A virus is a pandemic of a new strain of influenza virus [1] identified in April 2009, commonly referred to as ‘‘swine flu’’
3) The newly designed adamantanebased inhibitors based on the modeled structure of H1N1-M2 proton channel have two pharmacophore groups, which act like a ‘‘barrel hoop’’, holding two adjacent helices of the H1N1-M2 tetramer through the two pharmacophore groups outside the channel
To build the three dimensional structure of GQ385303, the high-resolution nuclear magnetic resonance (NMR) structure of M2 proton channel [16] with the PDB code of 2RLF was adopted as a template, which was determined for the M2 channel isolated from the Udorn strain of human influenza virus

Summary

Introduction

The outbreak of H1N1 influenza A virus is a pandemic of a new strain of influenza virus [1] identified in April 2009, commonly referred to as ‘‘swine flu’’. The H1N1 influenza virus is quite familiar to us because it had caused the 1918–1919 Spain pandemic that had infected 5% of the world population and resulted in 20–50 million deaths worldwide [1]. The even worse news is that cases were reported that several strains of H1N1 influenza A viruses were resistant to oseltamivir (Tamiflu). M2 proton channel of H1N1 influenza A virus is the target protein of anti-flu drugs amantadine and rimantadine. The NMR structure of the M2 channel protein determined by Schnell and Chou (Nature, 2008, 451, 591–595) may help people to solve the drug-resistant problem and develop more powerful new drugs against H1N1 influenza virus

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