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Influenza A viruses are important human respiratory pathogens associated with high morbidity and mortality as well as enormous social and economic burden. Nevertheless, the currently available clinical options for controlling influenza are very limited. Among the potentially relevant targets for the anti-influenza therapy, the viral M2 proton channel seems quite promising in spite of the spread of resistance to its classical aminoadamantane inhibitors. We have developed [1] a general approach to the design of ligands interacting with multiple labile targets. The dynamic structures of the three primary M2 target variants, wild-type, S31N (see Figure) and V27A, were modeled by molecular dynamics and thoroughly analyzed in order to define the inhibitor binding sites. A number of potential broad-spectrum inhibitors were identified by molecular docking and the binding modes and probable mechanisms of action of promising compounds were clarified using the molecular dynamics simulation of the channel-inhibitor complexes. In addition, experimental confirmation of activity for some of the inhibitors was obtained. The proposed approach is also suitable for the design of ligands interacting with other multiple labile targets.