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Linh Tran

Drug inhibition mechanisms of M2 channel proteins

Developing an understanding the mechanisms involved in the inhibition of M2 channel proteins is essential for defining a basic research strategy and conducting a drug development program against this target. During the past 10 years, however, there have been several conflicting and incomplete reports in the literature pertaining to the mechanism of M2 protein inhibition, and the exact mechanism of inhibition remains unclear. The exact location of the functional adamantane binding site had also been a source of controversy (Pielak et al. 2009), and two mechanisms have been proposed based on experimental structures, including (1) the pore-block mechanism, which was revealed by an X-ray structure (Stouffer et al. 2008); and (2) the allosteric mechanism, which was revealed by an NMR structure (Schnell and Chou 2008). The importance of computer-aided drug design has grown significantly in terms of its contribution to the drug development process (Sukumar and Das 2011; Andricopulo et al. 2009; Laurie and Jackson 2006). Furthermore, numerous reports have demonstrated that theoretical computational studies, including molecular modeling, molecular docking, molecular dynamics simulations, phylogenetic analysis, quantum mechanical calculations, pharmacophore modeling, QSAR, and bioinformatics techniques can provide useful information for research in drug development (Wang and Chou 2012; Du et al. 2010; Nguyen et al. 2009; Le and Leluk 2011). Several computational studies have been conducted on the mechanisms associated with M2 channel proteins, and the results of these studies have provided valuable insights into the activity of the M2 channel proteins and enhanced efforts towards the targeting of M2 channel proteins through rational drug design.