The M2 protein of the influenza A virus, responsible for flu, is a homotetramer transmembrane protein, forming a transmembrane ion channel, where His 37s act as pH sensors and Trp 41s and Asp 44s act as channel gates. Opening of this channel leads to transfer of virus RNA into the human host. Thus, blocking this transfer is an important pharmaceutical strategy to stop infection. As a result of viral drug resistance, commercially available channel inhibitors, rimantadine (RIM) and amantadine (AMA), are not as effective as they used to be. Understanding binding sites and outcomes of binding will lead to new inhibitor design studies. Here, utilizing molecular docking with classical and constant pH molecular dynamics simulations, two novel binding sites for RIM and AMA molecules were revealed. Both structural and chemical effects of inhibitors on M2 protein on the closed, inactive M2 channel structure were investigated. Upon binding of the inhibitor molecules, decrease in ion channel cross-distances was observed. Meanwhile, RIM binding did not alter protonation of His 37s and Asp 44s, whereas AMA binding drastically increased the protonation population of two residues from different monomers, creating a more basic channel at physiological pH.