Background: The influenza A virus M2 proton channel plays a critical
role in its life cycle. However, known M2 inhibitors have lost their clinical efficacy
due to the spread of resistant mutant channels. Thus, the search for broad-spectrum
M2 channel inhibitors is of great importance.
Objective: The goal of the present work was to develop a general approach
supporting the design of ligands interacting with multiple labile targets and to
propose on its basis the potential broad-spectrum inhibitors of the M2 proton channel.
Method: The dynamic dimer-of-dimers structures of the three primary M2 target variants, wild-type, S31N and V27A,
were modeled by molecular dynamics and thoroughly analyzed in order to define the inhibitor binding sites. The potential
inhibitor structures were identified by molecular docking and their binding was verified by molecular dynamics
Results: The binding sites of the M2 proton channel inhibitors were analyzed, a number of potential broad-spectrum
inhibitors were identified and the binding modes and probable mechanisms of action of one promising compound were
Conclusion: Using the molecular dynamics and molecular docking techniques, we have refined the dynamic dimer-ofdimers
structures of the WT, S31N and V27A variants of the M2 proton channel of the influenza A virus, analyzed the
inhibitor binding sites, identified a number of potential broad-spectrum inhibitor structures targeting them, and clarified
the binding modes and probable mechanisms of action of one promising compound. The proposed approach is also
suitable for the design of ligands interacting with other multiple labile targets.