Abstract
The 2009 influenza A virus pandemic, with high level of drug resistance reported, has highlighted the urgent need of more effective anti-influenza drugs. M2 channel proteins on the influenza A virus membrane have emerged as an efficient structure-based drug design target since variety of M2 channel protein structures were constructed by different experiment methods to generate the high resolution of crystal, solution NMR and solid-state NMR structure. In an effort to facilitate the future design of M2 channel inhibitors, the binding modes of 200 Adamantane-based drugs in four different types of M2 channel protein structures were evaluated by the critical interactions in terms of ligand binding affinity. The molecular docking results and statistic testing of binding affinity showed that the effect of each representative type from M2 channel protein structures was significantly different. Moreover, pharmacophore analysis revealed that there are two mechanisms of binding interactions to critical residues, Ser31 in holo structures and Ala30 in apo structures, respectively. Molecular docking studies, drug-like filters, and structure-based pharmacophore approaches successfully led us identifying the final hits reduced the false positives and false negatives in strategy of designing new potential group of future M2 channel inhibitors.
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Acknowledgments
The work was funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 106.01-2012.66. Computing resources and support provided by the Institute for Computational Science and Technology—Ho Chi Minh City is gratefully acknowledged.
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Nhut Tran and Linh Tran contributed equally to this study.
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Tran, N., Tran, L. & Le, L. Strategy in structure-based drug design for influenza A virus targeting M2 channel proteins. Med Chem Res 22, 6078–6088 (2013). https://doi.org/10.1007/s00044-013-0599-z
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DOI: https://doi.org/10.1007/s00044-013-0599-z