Computational design of drug candidates for influenza A virus subtype H1N1 by inhibiting the viral neuraminidase-1 enzyme

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It is critical to seek potential alternative treatments for H1N1 infections by inhibiting neuraminidase-1 enzyme. One of the viable options for inhibiting the activity of neuraminidase- 1 is peptide drug design. In order to increase peptide stability, cyclization is necessary to prevent its digestion by protease enzyme. Cyclization of peptide ligands by formation of disulfide bridges is preferable for designing inhibitors of neuraminidase-1 because of their high activity and specificity. Here we designed ligands by using molecular docking, drug scan and dynamics computational methods. Based on our docking results, short polypeptides of cystein-arginine-methionine-tyrosine- -proline-cysteine (CRMYPC) and cysteine-arginine-aspargine- phenylalanine-proline-cysteine (CRNFPC) have good residual interactions with the target and the binding energy ΔGbinding of -31.7402 and -31.0144 kcal mol-1, respectively. These values are much lower than those of the standards, and it means that both ligands are more accessible to ligand-receptor binding. Based on drug scan results, both of these ligands are neither mutagenic nor carcinogenic. They also show good oral bioavailability. Moreover, both ligands show relatively stable molecular dynamics progression of RMSD vs. time plot. However, based on our metods, the CRMYPC ligand has sufficient hydrogen bonding interactions with residues of the active side of neuraminidase-1 and can be therefore proposed as a potential inhibitor of neuraminidase-1

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  • 1. J. K. Taubenberger and D. M. Morens 1918 Influenza: the mother of all pandemic Emerg. Infect. Dis. 12 (2006) 15-22; DOI: 10.3201/eid1201.050979.

  • 2. P. Auewarakul O. Suptawiwat A. Kongchanagul C. Sangma Y. Suzuki K. Ungchusak S. Louisirirotchanakul H. Lerdsamran P. Pooruk A. Thitithanyanont C. Pittayawonganon C.-T. Guo H. Hiramatsu W. Jampangern S. Chunsutthiwat and P. Puthavathana An avian influenza H5N1 virus that binds to a human-type receptor J. Virol. 81 (2007) 9950-9955; DOI: 10.1128/ JVI.00468-07.

  • 3. I. V. Alymova A. Portner V. P. Mishin J. A. McCullers P. Freiden and G. L. Taylor Receptor- -binding specificity of the human parainfluenza virus type 1 hemagglutinin-neuraminidase glycoprotein Glycobiology 22 (2012) 174-180; DOI: 10.1093/glycob/cwr112.

  • 4. S.-Q. Wang Q.-S. Du R.-B. Huang D.-W. Zhang and K.-C. Chou Insights from investigating the interaction of oseltamivir (Tamiflu) with neuraminidase of the 2009 H1N1 swine flu virus Biochem. Biophys. Res. Commun. 386 (2009) 432-436; DOI: 10.1016/j.bbrc.2009.06.016.

  • 5. H. T. Nguyen T. G. Sheu V. P. Mishin A. I. Klimov and L. V Gubareva Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays Antimicrob. Agents Chemother. 54 (2010) 3671-3677; DOI: 10.1128/ AAC.00581-10.

  • 6. N. J. Dharan L. V. Gubareva J. J. Meyer M. Okomo-Adhiambo R. C. McClinton S. A. Marshall K. St George S. Epperson L. Brammer A. I. Klimov J. S. Bresee and A. M. Fry Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States JAMA 301 (2009) 1034-1041; DOI: 10.1001/jama.2009.294.

  • 7. T. Kolomin M. Shadrina P. Slominsky S. Limborska and N. Myasoedov A new generation of drugs: Synthetic peptides based on natural regulatory peptides Neurosci. Med. 4 (2013) 223-252; DOI: 10.4326/nm.2013.44035.

  • 8. C. D. Fjell J. A. Hiss R. E. W. Hancock and G. Schneider Designing antimicrobial peptides: form follows function Nat. Rev. Drug Discov. 11 (2012) 37-51; DOI: 10.1038/nrd3591.

  • 9. S. Riedl D. Zweytick and K. Lohner Membrane-active host defense peptides - challenges and perspectives for the development of novel anticancer drugs Chem. Phys. Lipids 164 (2011) 766-781; DOI: 10.1016/j.chemphyslip.2011.09.004.

  • 10. P. Vlieghe V. Lisowski J. Martinez and M. Khrestchatisky Synthetic therapeutic peptides: science and market Drug. Disc. Today 15 (2010) 40-56; DOI: 10.1016/j.drudis.2009.10.009.

  • 11. R. Benigni and C. Bossa Structure alerts for carcinogenicity and the Salmonella assay system: a novel insight through the chemical relational databases technology Mutat. Res. 659 (2008) 248-261; DOI: 10.1016/j.mrrev.2008.05.003.

  • 12. U. S. F. Tambunan N. Amri and A. A. Parikesit In silico design of cyclic peptides as influenza virus a subtype H1N1 neuraminidase inhibitor African J. Biotechnol. 11 (2012) 11474-11491; DOI: 10.5897/AJB11.4094.

  • 13. C. A. Lipinski F. Lombardo B. W. Dominy and P. J. Feeney Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Deliv. Rev. 46 (2001) 3-26.

  • 14. S.-L. Du H. Pan W.-Y. Lu J. Wang J. Wu and J.-Y. Wang Cyclic Arg-Gly-Asp peptide-labeled liposomes for targeting drug therapy of hepatic fibrosis in rats J. Pharmacol. Exp. Ther. 322 (2007) 560-568; DOI: 10.1124/jpet.107.122481.

  • 15. T. R. White C. M. Renzelman A. C. Rand T. Rezai C. M. McEwen V. M. Gelev R. A. Turner R. G. Linington S. S. F. Leung A. S. Kalgutkar J. N. Bauman Y. Zhang S. Liras D. A. Price A. M. Mathiowetz M. P. Jacobson and R. S. Lokey On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds Nat. Chem. Biol. 7 (2011) 810-817; DOI: 10.1038/nchembio. 664.

  • 16. M. Brvar A. Perdih M. Renko G. Anderluh D. Turk and T. Solmajer Structure-based discovery of substituted 45’-bithiazoles as novel DNA gyrase inhibitors J. Med. Chem. 55 (2012) 6413-6426; DOI: 10.1021/jm300395d.

  • 17. C. Liao M. Sitzmann A. Pugliese and M. C. Nicklaus Software and resources for computational medicinal chemistry Future Med. Chem. 3 (2011) 1057-1085; DOI: 10.4155/fmc.11.63.

  • 18. D. L. Wheeler T. Barrett D. A. Benson S. H. Bryant K. Canese V. Chetvernin D. M. Church M. DiCuccio R. Edgar S. Federhen L. Y. Geer Y. Kapustin O. Khovayko D. Landsman D. J. Lipman T. L. Madden D. R. Maglott J. Ostell K. D. Pruitt G. D. Schuler L. M. Schriml E. Sequeira S. T. Sherry K. Sirotkin A. Souvorov G. Starchenko T. O. Suzek R. Tatusov T. A. Tatusova L. Wagner and E. Yaschenko Database resources of the National Center for Biotechnology Information Nucl. Acids Res. 35 (2007) D5-D12; DOI: 10.1093/nar/gkl1031.

  • 19. U. S. F. Tambunan R. Harganingtyas and A. A. Parikesit In silico modification of (1R 2R 3R 5S)-(-)-isopinocampheylamine as inhibitors of M2 proton channel in Influenza A virus subtype H1N1 using the molecular docking approach Trends Bioinform. 5 (2012) 25-46; DOI: 10.3923/ tb.2012.25.46.

  • 20. U. S. F. Tambunan N. Bramantya and A. A. Parikesit In silico modification of suberoylanilide hydroxamic acid (SAHA) as potential inhibitor for class II histone deacetylase (HDAC) BMC Bioinformatics 12 (Suppl. 13) (2011) S23-S38; DOI:10.1186/1471-2105-12-S13-S23.

  • 21. R. Benigni and C. Bossa Structure alerts for carcinogenicity and the Salmonella assay system: a novel insight through the chemical relational databases technology Mutat. Res. 659 (2008) 248-261; DOI: 10.1016/j.mrrev.2008.05.003.

  • 22. T. Sander J. Freyss M. von Korff J. R. Reich and C. Rufener OSIRIS an entirely in-house developed drug discovery informatics system J. Chem. Inf. Model. 49 (2009) 232-246; DOI: 10.1021/ ci800305f.

  • 23. D. Lagorce O. Sperandio H. Galons M. A. Miteva and B. O. Villoutreix FAF-drugs2: free ADME/ tox filtering tool to assist drug discovery and chemical biology projects BMC Bioinformatics 9 (2008) 396-405; DOI: 10.1186/1471-2105-9-396.

  • 24. A. D. MacKerell N. Banavali and N. Foloppe Development and current status of the CHARMM force field for nucleic acids Biopolymers 56 (2000) 257-265; DOI: 10.1002/1097-0282 (2000)56:4< 257::AID-BIP10029>3.0.CO;2-W.

  • 25. Y. Shen M. K. Gilson and B. Tidor Charge optimization theory for induced-fit ligands J. Chem. Theory Comput. 8 (2012) 4580-4592; DOI: 10.1021/ct200931c.

  • 26. J. R. Williams A. L. Khandoga P. Goyal J. I. Fells D. H. Perygin W. Siess A. L. Parrill G. Tigyi and Y. Fujiwara Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation J. Biol. Chem. 284 (2009) 17304-17319; DOI: 10.1074/jbc. M109.003194.

  • 27. G. L. Warren C. W. Andrews A.-M. Capelli B. Clarke J. LaLonde M. H. Lambert M. Lindvall N. Nevins S. F. Semus S. Senger G. Tedesco I. D. Wall J. M. Woolven C. E. Peishoff and M. S. Head A critical assessment of docking programs and scoring functions J. Med. Chem.49 (2006) 5912-5931; DOI: 10.1021/jm050362n.

  • 28. Y. Modis S. Ogata D. Clements and S. C. Harrison A ligand-binding pocket in the dengue virus envelope glycoprotein Proc. Natl. Acad. Sci. USA 100 (2003) 6986-6991; DOI: 10.1073/pnas. 0832193100.

  • 29. M. Takano T. P. Terada and M. Sasai Unidirectional Brownian motion observed in an in silico single molecule experiment of an actomyosin motor Proc. Natl. Acad. Sci. USA 107 (2010) 7769-7774; DOI: 10.1073/pnas.0911830107.

  • 30. S. Rogers R. Wells and M. Rechsteiner Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis Science 234 (1986) 364-368 DOI: 10.1126/science.2876518.

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