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Recent progress and challenges in the computer-aided design of inhibitors for influenza A M2 channel proteins

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Abstract

The M2 channel protein has become an attractive target for the design of new drugs against influenza because it plays a crucial role in the replication cycle of influenza A virus. Several adamantane-based drugs have recently been developed to inhibit the activity of the M2 channel and overcome the drug resistance issues observed in amantadine and rimantadine. Computer-aided drug design continues to play a critical role in the drug discovery process in terms of its contribution to the identification and development of new therapeutic agents. Scientists working in this field are currently facing significant challenges with regard to creating novel platforms capable of enhancing our understanding of these proteins, with computational techniques being used to search for new potential drugs against influenza. This review provides a summary of recent progress in drug discovery toward the development therapeutic agents targeting M2 channel proteins. It is hoped that this review will stimulate the development of new strategies for overcoming drug resistance problems and encourage the design of new and improved drugs against influenza A virus.

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References

  • Acharya R, Carnevale V, Fiorin G, Levine BG, Polishchuk AL, Balannik V, Samish I, Lamb RA, Pinto LH, DeGrado WF, Klein ML (2010) Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus. Proc Natl Acad Sci USA 107(34):15075–15080. doi:10.1073/pnas.1007071107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Andricopulo AD, Salum LB, Abraham DJ (2009) Structure-based drug design strategies in medicinal chemistry. Curr Top Med Chem 9(9):771–790

    Article  CAS  PubMed  Google Scholar 

  • Balannik V, Wang J, Ohigashi Y, Jing X, Magavern E, Lamb RA, Degrado WF, Pinto LH (2009) Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus. Biochemistry 48(50):11872–11882. doi:10.1021/bi9014488

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Balgi AD, Wang J, Cheng DY, Ma C, Pfeifer TA, Shimizu Y, Anderson HJ, Pinto LH, Lamb RA, DeGrado WF, Roberge M (2013) Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay. PLoS One 8(2):e55271. doi:10.1371/journal.pone.0055271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Betakova T, Ciampor F, Hay AJ (2005) Influence of residue 44 on the activity of the M2 proton channel of influenza A virus. J Gen Virol 86(Pt 1):181–184. doi:10.1099/vir.0.80358-0

    Article  CAS  PubMed  Google Scholar 

  • Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI (2006) Adamantane resistance among influenza A viruses isolated early during the 2005–2006 influenza season in the United States. JAMA 295(8):891–894. doi:10.1001/jama.295.8.joc60020

    Article  CAS  PubMed  Google Scholar 

  • Cady SD, Luo W, Hu F, Hong M (2009) Structure and function of the influenza A M2 proton channel. Biochemistry 48(31):7356–7364. doi:10.1021/bi9008837

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cady SD, Schmidt-Rohr K, Wang J, Soto CS, Degrado WF, Hong M (2010) Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. Nature 463(7281):689–692. doi:10.1038/nature08722

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cavasotto CN, Orry AJ (2007) Ligand docking and structure-based virtual screening in drug discovery. Curr Top Med Chem 7(10):1006–1014

    Article  CAS  PubMed  Google Scholar 

  • Chang SS, Huang HJ, Chen CY (2011) Two birds with one stone? Possible dual-targeting H1N1 inhibitors from traditional Chinese medicine. PLoS Comput Biol 7(12):e1002315. doi:10.1371/journal.pcbi.1002315

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cox NJ, Subbarao K (2000) Global epidemiology of influenza: past and present. Annu Rev Med 51:407–421. doi:10.1146/annurev.med.51.1.407

    Article  CAS  PubMed  Google Scholar 

  • Cross TA, Dong H, Sharma M, Busath DD, Zhou HX (2012) M2 protein from influenza A: from multiple structures to biophysical and functional insights. Curr Opin Virol 2(2):128–133. doi:10.1016/j.coviro.2012.01.005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Deyde VM, Xu X, Bright RA, Shaw M, Smith CB, Zhang Y, Shu Y, Gubareva LV, Cox NJ, Klimov AI (2007) Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis 196(2):249–257. doi:10.1086/518936

    Article  CAS  PubMed  Google Scholar 

  • Du QS, Huang RB (2012) Recent progress in computational approaches to studying the M2 proton channel and its implication to drug design against influenza viruses. Curr Protein Pept Sci 13(3):205–210

    Article  CAS  PubMed  Google Scholar 

  • Du QS, Huang RB, Wang CH, Li XM, Chou KC (2009) Energetic analysis of the two controversial drug binding sites of the M2 proton channel in influenza A virus. J Theor Biol 259(1):159–164. doi:10.1016/j.jtbi.2009.03.003

    Article  CAS  PubMed  Google Scholar 

  • Du QS, Huang RB, Wang SQ, Chou KC (2010) Designing inhibitors of M2 proton channel against H1N1 swine influenza virus. PLoS One 5(2):e9388. doi:10.1371/journal.pone.0009388

    Article  PubMed Central  PubMed  Google Scholar 

  • Du J, Cross TA, Zhou HX (2012) Recent progress in structure-based anti-influenza drug design. Drug Discov Today 17(19–20):1111–1120. doi:10.1016/j.drudis.2012.06.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Duque MD, Ma C, Torres E, Wang J, Naesens L, Juarez-Jimenez J, Camps P, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vazquez S (2011) Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus. J Med Chem 54(8):2646–2657. doi:10.1021/jm101334y

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Heikamp K, Bajorath J (2013) The future of virtual compound screening. Chem Biol Drug Des 81(1):33–40. doi:10.1111/cbdd.12054

    Article  CAS  PubMed  Google Scholar 

  • Hu J, Asbury T, Achuthan S, Li C, Bertram R, Quine JR, Fu R, Cross TA (2007) Backbone structure of the amantadine-blocked trans-membrane domain M2 proton channel from Influenza A virus. Biophys J 92(12):4335–4343. doi:10.1529/biophysj.106.090183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hu W, Zeng S, Li C, Jie Y, Li Z, Chen L (2010) Identification of hits as matrix-2 protein inhibitors through the focused screening of a small primary amine library. J Med Chem 53(9):3831–3834. doi:10.1021/jm901664a

    Article  CAS  PubMed  Google Scholar 

  • Intharathep P, Laohpongspaisan C, Rungrotmongkol T, Loisruangsin A, Malaisree M, Decha P, Aruksakunwong O, Chuenpennit K, Kaiyawet N, Sompornpisut P, Pianwanit S, Hannongbua S (2008) How amantadine and rimantadine inhibit proton transport in the M2 protein channel. J Mol Graph Model 27(3):342–348. doi:10.1016/j.jmgm.2008.06.002

    Article  CAS  PubMed  Google Scholar 

  • Jimenez S, Torres M, Vizuete M, Sanchez-Varo R, Sanchez-Mejias E, Trujillo-Estrada L, Carmona-Cuenca I, Caballero C, Ruano D, Gutierrez A, Vitorica J (2011) Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3 K)/Akt-GSK-3beta pathway in Alzheimer mouse model. J Biol Chem 286(21):18414–18425. doi:10.1074/jbc.M110.209718

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kolocouris N, Zoidis G, Foscolos GB, Fytas G, Prathalingham SR, Kelly JM, Naesens L, De Clercq E (2007) Design and synthesis of bioactive adamantane spiro heterocycles. Bioorg Med Chem Lett 17(15):4358–4362. doi:10.1016/j.bmcl.2007.04.108

    Article  CAS  PubMed  Google Scholar 

  • Kurtz S, Luo G, Hahnenberger KM, Brooks C, Gecha O, Ingalls K, Numata K, Krystal M (1995) Growth impairment resulting from expression of influenza virus M2 protein in Saccharomyces cerevisiae: identification of a novel inhibitor of influenza virus. Antimicrob Agents Chemother 39(10):2204–2209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lai C-Y, Chang T–T, Sun M-F, Chen H-Y, Tsai F-J, Lin J-G, Chen CY-C (2011) Molecular dynamics analysis of potent inhibitors of M2 proton channel against H1N1 swine influenza virus. Mol Simul 37(3):250–256. doi:10.1080/08927022.2010.543972

    Article  CAS  Google Scholar 

  • Laohpongspaisan C, Rungrotmongkol T, Intharathep P, Malaisree M, Decha P, Aruksakunwong O, Sompornpisut P, Hannongbua S (2009) Why amantadine loses its function in influenza m2 mutants: MD simulations. J Chem Inf Model 49(4):847–852. doi:10.1021/ci800267a

    Article  CAS  PubMed  Google Scholar 

  • Laurie AT, Jackson RM (2006) Methods for the prediction of protein-ligand binding sites for structure-based drug design and virtual ligand screening. Curr Protein Pept Sci 7(5):395–406

    Article  CAS  PubMed  Google Scholar 

  • Le L, Leluk J (2011) Study on phylogenetic relationships, variability, and correlated mutations in M2 proteins of influenza virus A. PLoS ONE 6(8):e22970. doi:10.1371/journal.pone.0022970

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li C, Long Y, Lin Z, Jie Y, Xiao Y, Yang L, Sun J, Ren Y, Chen L, Li Z (2013) New strategy for high throughput screening of anti-influenza virus m2 ion channel inhibitors. Curr Pharm Des 19(28):5146–5155

    Article  CAS  PubMed  Google Scholar 

  • Lin CH, Chang TT, Sun MF, Chen HY, Tsai FJ, Chang KL, Fisher M, Chen CY (2011) Potent inhibitor design against H1N1 swine influenza: structure-based and molecular dynamics analysis for M2 inhibitors from traditional Chinese medicine database. J Biomol Struct Dyn 28(4):471–482. doi:10.1080/07391102.2011.10508589

    Article  CAS  PubMed  Google Scholar 

  • Lyne PD (2002) Structure-based virtual screening: an overview. Drug Discov Today 7(20):1047–1055

    Article  CAS  PubMed  Google Scholar 

  • Nguyen H, Le L, Truong TN (2009) Top-hits for H1N1pdm Identified by Virtual Screening Using Ensemble-based Docking. PLoS Curr 3:RRN1030. doi:10.1371/currents.RRN1030

    PubMed  Google Scholar 

  • Nguyen TH, Hoang D, Le L (2013) Binding Drugs on Two Position of M2 Proton Channel and Its Mutants. In: Toi VV, Toan NB, Dang Khoa TQ, Lien Phuong TH (eds) 4th International Conference on Biomedical Engineering in Vietnam, vol 40. IFMBE Proceedings. Springer Berlin Heidelberg, pp 384-390. doi:10.1007/978-3-642-32183-2_93

  • Pielak RM, Chou JJ (2011) Influenza M2 proton channels. Biochim Biophys Acta 1808 2:522–529. doi:10.1016/j.bbamem.2010.04.015

    Article  Google Scholar 

  • Pielak RM, Schnell JR, Chou JJ (2009) Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proc Natl Acad Sci USA 106(18):7379–7384. doi:10.1073/pnas.0902548106

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pinto LH, Holsinger LJ, Lamb RA (1992) Influenza virus M2 protein has ion channel activity. Cell 69(3):517–528 0092-8674(92)90452-I

    Article  CAS  PubMed  Google Scholar 

  • Pissawong T, Maneewatch S, Thueng-In K, Srimanote P, Dong-din-on F, Thanongsaksrikul J, Songserm T, Tongtawe P, Bangphoomi K, Chaicumpa W (2013) Human monoclonal ScFv that bind to different functional domains of M2 and inhibit H5N1 influenza virus replication. Virol J 10:148. doi:10.1186/1743-422X-10-148

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reese KA, Lupfer C, Johnson RC, Mitev GM, Mullen VM, Geller BL, Pastey M (2013) A Novel Lactococcal Vaccine Expressing a Peptide from the M2 Antigen of H5N2 Highly Pathogenic Avian Influenza A Virus Prolongs Survival of Vaccinated Chickens. Vet Med Int 2013:316926. doi:10.1155/2013/316926

    Article  PubMed Central  PubMed  Google Scholar 

  • Rungrotmongkol T, Intharathep P, Malaisree M, Nunthaboot N, Kaiyawet N, Sompornpisut P, Payungporn S, Poovorawan Y, Hannongbua S (2009) Susceptibility of antiviral drugs against 2009 influenza A (H1N1) virus. Biochem Biophys Res Commun 385(3):390–394. doi:10.1016/j.bbrc.2009.05.066

    Article  CAS  PubMed  Google Scholar 

  • Schnell JR, Chou JJ (2008) Structure and mechanism of the M2 proton channel of influenza A virus. Nature 451(7178):591–595. doi:10.1038/nature06531

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sharma M, Yi M, Dong H, Qin H, Peterson E, Busath DD, Zhou HX, Cross TA (2010) Insight into the mechanism of the influenza A proton channel from a structure in a lipid bilayer. Science 330(6003):509–512. doi:10.1126/science.1191750

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Simonsen L, Viboud C, Grenfell BT, Dushoff J, Jennings L, Smit M, Macken C, Hata M, Gog J, Miller MA, Holmes EC (2007) The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance. Mol Biol Evol 24(8):1811–1820. doi:10.1093/molbev/msm103

    Article  CAS  PubMed  Google Scholar 

  • Stamatiou G, Kolocouris A, Kolocouris N, Fytas G, Foscolos GB, Neyts J, De Clercq E (2001) Novel 3-(2-adamantyl)pyrrolidines with potent activity against influenza A virus-identification of aminoadamantane derivatives bearing two pharmacophoric amine groups. Bioorg Med Chem Lett 11(16):2137–2142

    Article  CAS  PubMed  Google Scholar 

  • Stouffer AL, Acharya R, Salom D, Levine AS, Di Costanzo L, Soto CS, Tereshko V, Nanda V, Stayrook S, DeGrado WF (2008) Structural basis for the function and inhibition of an influenza virus proton channel. Nature 451(7178):596–599. doi:10.1038/nature06528

    Article  CAS  PubMed  Google Scholar 

  • Sukumar N, Das S (2011) Current trends in virtual high throughput screening using ligand-based and structure-based methods. Comb Chem High Throughput Screen 14(10):872–888

    Article  CAS  PubMed  Google Scholar 

  • Tataridis D, Fytas G, Kolocouris A, Fytas C, Kolocouris N, Foscolos GB, Padalko E, Neyts J, De Clercq E (2007) Influence of an additional 2-amino substituent of the 1-aminoethyl pharmacophore group on the potency of rimantadine against influenza virus A. Bioorg Med Chem Lett 17(3):692–696

    Article  CAS  PubMed  Google Scholar 

  • Tran L, Choi SB, Al-Najjar BO, Yusuf M, Wahab HA, Le L (2011) Discovery of potential M2 channel inhibitors based on the amantadine scaffold via virtual screening and pharmacophore modeling. Molecules 16(12):10227–10255. doi:10.3390/molecules161210227

    Article  CAS  PubMed  Google Scholar 

  • Tran N, Tran L, Le L (2013) Strategy in structure-based drug design for influenza A virus targeting M2 channel proteins. Med Chem Res 22(12):6078–6088. doi:10.1007/s00044-013-0599-z

    Google Scholar 

  • Wang JF, Chou KC (2012) Recent advances in computational studies on influenza a virus M2 proton channel. Mini Rev Med Chem 12(10):971–978

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Cady SD, Balannik V, Pinto LH, DeGrado WF, Hong M (2009) Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. J Am Chem Soc 131(23):8066–8076. doi:10.1021/ja900063s

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Ma C, Balannik V, Pinto LH, Lamb RA, Degrado WF (2011a) Exploring the requirements for the hydrophobic scaffold and polar amine in inhibitors of M2 from influenza A Virus. ACS Med Chem Lett 2(4):307–312. doi:10.1021/ml100297w

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J, Ma C, Fiorin G, Carnevale V, Wang T, Hu F, Lamb RA, Pinto LH, Hong M, Klein ML, DeGrado WF (2011b) Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2. J Am Chem Soc 133(32):12834–12841. doi:10.1021/ja204969m

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J, Ma C, Wu Y, Lamb RA, Pinto LH, DeGrado WF (2011c) Exploring organosilane amines as potent inhibitors and structural probes of influenza a virus M2 proton channel. J Am Chem Soc 133(35):13844–13847. doi:10.1021/ja2050666

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J, Ma C, Jo H, Canturk B, Fiorin G, Pinto LH, Lamb RA, Klein ML, DeGrado WF (2013a) Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus. J Med Chem 56(7):2804–2812. doi:10.1021/jm301538e

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang J, Wu Y, Ma C, Fiorin G, Pinto LH, Lamb RA, Klein ML, Degrado WF (2013b) Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus. Proc Natl Acad Sci USA 110(4):1315–1320. doi:10.1073/pnas.1216526110

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Waszkowycz B (2002) Structure-based approaches to drug design and virtual screening. Curr Opin Drug Discov Devel 5(3):407–413

    CAS  PubMed  Google Scholar 

  • Wei H, Wang CH, Du QS, Meng J, Chou KC (2009) Investigation into adamantane-based M2 inhibitors with FB-QSAR. Med Chem 5(4):305–317

    Article  CAS  PubMed  Google Scholar 

  • Williams JK, Tietze D, Wang J, Wu Y, DeGrado WF, Hong M (2013a) Drug-induced conformational and dynamical changes of the S31N mutant of the influenza M2 proton channel investigated by solid-state NMR. J Am Chem Soc 135(26):9885–9897. doi:10.1021/ja4041412

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Williams JK, Zhang Y, Schmidt-Rohr K, Hong M (2013b) pH-dependent conformation, dynamics, and aromatic interaction of the gating tryptophan residue of the influenza M2 proton channel from solid-state NMR. Biophys J 104(8):1698–1708. doi:10.1016/j.bpj.2013.02.054

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wilson GL, Lill MA (2011) Integrating structure-based and ligand-based approaches for computational drug design. Future Med Chem 3(6):735–750. doi:10.4155/fmc.11.18

    Article  CAS  PubMed  Google Scholar 

  • Winkler FK, Banner DW, Bohm HJ (2001) Structure-based approaches in modern drug discovery research. Ernst Schering Res Found Workshop 34:123–142

    CAS  PubMed  Google Scholar 

  • Witter R, Nozirov F, Sternberg U, Cross TA, Ulrich AS, Fu R (2008) Solid-state 19F NMR spectroscopy reveals that Trp41 participates in the gating mechanism of the M2 proton channel of influenza A virus. J Am Chem Soc 130(3):918–924. doi:10.1021/ja0754305

    Article  CAS  PubMed  Google Scholar 

  • Yi M, Cross TA, Zhou HX (2008) A secondary gate as a mechanism for inhibition of the M2 proton channel by amantadine. J Phys Chem B 112(27):7977–7979. doi:10.1021/jp800171m

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zarubaev VV, Golod EL, Anfimov PM, Shtro AA, Saraev VV, Gavrilov AS, Logvinov AV, Kiselev OI (2010) Synthesis and anti-viral activity of azolo-adamantanes against influenza A virus. Bioorg Med Chem 18(2):839–848. doi:10.1016/j.bmc.2009.11.047

    Article  CAS  PubMed  Google Scholar 

  • Zhao X, Li C, Zeng S, Hu W (2011) Discovery of highly potent agents against influenza A virus. Eur J Med Chem 46(1):52–57. doi:10.1016/j.ejmech.2010.10.010

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Vietnam’s National Foundation for Science and Technology Development (NAFOSTED) through grant numbers 106.01–2012.66. The computing resources and support provided by the Institute for Computational Science and Technology, Ho Chi Minh City is gratefully acknowledged.

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  1. School of Biotechnology, Ho Chi Minh International University, Ho Chi Minh City, Vietnam

    Linh Tran & Ly Le

  2. Life Science Laboratory, Institute for Computational Science and Technology, Ho Chi Minh City, Vietnam

    Linh Tran & Ly Le

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Tran, L., Le, L. Recent progress and challenges in the computer-aided design of inhibitors for influenza A M2 channel proteins. Med Chem Res 23, 3607–3616 (2014). https://doi.org/10.1007/s00044-014-0964-6

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