Skip to main content

Docking studies towards exploring antiviral compounds against envelope protein of yellow fever virus


Yellow fever is among one of the most lethal viral diseases for which approved antiviral therapies were yet to be discovered. Herein, functional assignment of complete YFV proteome was done through support vector machine. Major envelope (E) protein that mediates entry of YFV into host cell was selected as a potent molecular target. Three dimensional structure of the molecular target was predicted using Modeller9v7. The model was optimized in Maestro9.0 applying OPLS AA force field and was evaluated using PROCHECK, ProSA, ProQ and Profile 3D. The BOG pocket residues Val48, Glu197, Thr200, Ile204, Thr265, Thr268 and Gly278 were located in YFV E protein using SiteMap2.3. More than one million compounds of Ligandinfo Meta database were explored using a computational virtual screening protocol targeting BOG pocket of the E protein. Finally, ten top ranked lead molecules with strong binding affinity to BOG pocket of YFV E protein were identified based on XP Gscore. Drug likeliness and comparative bioactivity analysis for these leads using QikProp3.2 had shown that these molecules would have the potential to act as better drug. Thus, the 10 lead molecules suggested in the present study would be of interest as promising starting point for designing antiviral compound against yellow fever.

This is a preview of subscription content, access via your institution.


  1. [1]

    Allison, S.L., Schalich, J., Stiasny, K., Mandl, C.W., Heinz, F.X. 2001. Mutational evidence for an internal fusion peptide in flavivirus envelope protein E. J Virol 75, 4268–4275.

    PubMed  Article  CAS  Google Scholar 

  2. [2]

    Allsop, A.E. 1998. New antibiotic discovery, novel screens, novel targets and impact of microbial genomics. Curr Opin Microbiol 64, 530–534.

    Article  Google Scholar 

  3. [3]

    Altschul, S.F., Madden, T.L., Schaffer, A.A., Zhang, J., Zhang, Z., Miller, W., Lipman, D.J. 1997. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res 25, 3389–3402.

    PubMed  Article  CAS  Google Scholar 

  4. [4]

    Anderson, R. 2003. Manipulation of cell surface molecules by flaviviruses. Adv Virus Res 59, 229–274.

    PubMed  Article  CAS  Google Scholar 

  5. [5]

    Beasley, D.W., Aaskov, J.G. 2001. Epitopes on the Dengue 1 virus envelope protein recognized by neutralizing IgM monoclonal antibodies. Virology 279, 447–458.

    PubMed  Article  CAS  Google Scholar 

  6. [6]

    Bell, J.R., Kinney, R.M., Trent, D.W., Lenches, E.M., Dalgarno, L., Strauss, J.H. 1985. Amino-terminal amino acid sequences of structural proteins of three flaviviruses. Virology 143, 224–229.

    PubMed  Article  CAS  Google Scholar 

  7. [7]

    Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E. 2000. The Protein Data Bank. Nucleic Acids Res 28, 235–242.

    PubMed  Article  CAS  Google Scholar 

  8. [8]

    Boege, U., Heinz, F.X., Wengler, G., Kunz, C. 1983. Amino acid compositions and amino-terminal sequences of the structural proteins of a flavivirus, European Tick-Borne encephalitis virus. Virology 126, 651–657.

    PubMed  Article  CAS  Google Scholar 

  9. [9]

    Bressanelli, S., Stiasny, K.S.L., Allison, S.L., Stura, E.A., Duquerroy, S., Lescar, J., Heinz, F.X., Rey, F.A. 2004. Structure of a flavivirus envelope glycoprotein in its low-pH-induced membrane fusion conformation. EMBO J 23, 728–738.

    PubMed  Article  CAS  Google Scholar 

  10. [10]

    Brooks, W., Daniel, K., Sung, S., Guida, W. 2008. Computational validation of the importance of absolute stereochemistry in virtual screening. J Chem Inf Model 48, 639–645.

    PubMed  Article  CAS  Google Scholar 

  11. [11]

    Cai, C.Z., Han, Z.L., Chen, X., Chen, Y.Z. 2003. SVMProt: Web-based support vector machine software for functional classification of a protein from its primary sequence. Nucleic Acids Res 31, 3692–3697.

    PubMed  Article  CAS  Google Scholar 

  12. [12]

    Carver, T., Bleasby, A. 2003. The design of Jemboss: a graphical user interface to EMBOSS. Bioinformatics 19, 1837–1843.

    PubMed  Article  CAS  Google Scholar 

  13. [13]

    Castle, E., Nowak, T., Leidner, U., Wengler, G., Wengler, G. 1985. Sequence analysis of the viral core protein and the membrane-associated proteins V1 and NV2 of the flavivirus West Nile virus and of the genome sequence for these proteins. Virology 145, 227–236.

    PubMed  Article  CAS  Google Scholar 

  14. [14]

    Castrignano, T., de Meo, P.D.O., Cozzetto, D., Talamo, I.G., Tramontano, A. 2006. The PMDB Protein Model Database. Nucleic Acids Res 34, 306–309.

    Article  Google Scholar 

  15. [15]

    Cecilia, D., Gould, E.A. 1991. Nucleotide changes responsible for loss of neuroinvasiveness in Japanese encephalitis virus neutralization resistant mutants. Virology 181, 70–77.

    PubMed  Article  CAS  Google Scholar 

  16. [16]

    Crill, W.D., Roehrig, J.T. 2001. Monoclonal antibodies that bind to domain III of Dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells. Virology 75, 7769–7773.

    Article  CAS  Google Scholar 

  17. [17]

    Deubel, V., Kinney, R.M., Trent, D.W. 1986. Nucleotide sequence and deduced amino acid sequence of the structural proteins of Dengue type 2 virus, Jamaican genotype. Virology 155, 365–377.

    PubMed  Article  CAS  Google Scholar 

  18. [18]

    Eswar, N., Eramian, D., Webb, B., Shen, M.Y., Sali, A. 2008. Protein structure modeling with MODELLER. Methods Mol Biol 426, 145–159.

    PubMed  Article  CAS  Google Scholar 

  19. [19]

    Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., Repasky, M.P., Knoll, E.H., Shelley, M., Perry, J.K., Shaw, D.E., Francis, P., Shenkin, P.S. 2004. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47, 1739–1749.

    PubMed  Article  CAS  Google Scholar 

  20. [20]

    Friesner, R.A., Murphy, R.B., Repasky, M.P., Frye, L.L., Greenwood, J.R., Halgren, T.A., Sanschagrin, P.C., Mainz, D.T. 2006. Extra precision glide docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49, 6177–6196.

    PubMed  Article  CAS  Google Scholar 

  21. [21]

    Goncalves, R.B., Mendes, Y.S., Soares, M.R., Katpally, U., Smith, T.J., Silva, J.L., Oliveira, A.C. 2007. VP4 protein from human rhinovirus 14 is released by pressure and locked in the capsid by the antiviral compound WIN. J Mol Biol 366, 295–306.

    PubMed  Article  CAS  Google Scholar 

  22. [22]

    Grotthuss, M.V., Pas, J., Rychlewski, L. 2003. Ligand-Info, searching for similar small compounds using index profiles. Bioinformatics 19, 1041–1042.

    Article  Google Scholar 

  23. [23]

    Halgren, T.A., Murphy, R.B., Friesner, R.A., Beard, H.S., Frye, L.L., Pollard, W.T., Banks, J.L. 2004. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47, 1750–1759.

    PubMed  Article  CAS  Google Scholar 

  24. [24]

    Hasegawa, H., Yoshida, M., Shiosaka, T., Fujita, S., Kobayashi, Y. 1992. Mutations in the envelope protein of Japanese encephalitis virus affect entry into cultured cells and virulence in mice. Virology 191, 158–165.

    PubMed  Article  CAS  Google Scholar 

  25. [25]

    Heinz, F.X. 1986. Epitope mapping of flavivirus glycoproteins. Adv Virus Res 31, 103–168.

    PubMed  Article  CAS  Google Scholar 

  26. [26]

    Heinz, F.X., Allison, S.A. 2000. Structures and mechanisms in flavivirus fusion. Adv Virus Res 55, 231–269.

    PubMed  Article  CAS  Google Scholar 

  27. [27]

    Hurrelbrink, R.J., McMinn, P.C. 2001. Attenuation of murray valley encephalitis virus by site-directed mutagenesis of the hinge and putative receptor-binding regions of the envelope protein. J Virology 75, 7692–7702.

    PubMed  Article  CAS  Google Scholar 

  28. [28]

    James, W. 2007. Aptamers in the virologists’ toolkit. J Gen Virol 88, 351–364.

    PubMed  Article  CAS  Google Scholar 

  29. [29]

    Jiang, W.R., Lowe, A., Higgs, S., Reid, H., Gould, E.A. 1993. Single amino acid codon changes detected in louping ill virus antibody-resistant mutants with reduced neurovirulence. J Gen Virol 74, 931–935.

    PubMed  Article  CAS  Google Scholar 

  30. [30]

    Jorgensen, W.L., Maxwell, D.S., Tirado-Rives, J. 1996. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118, 11225–11236.

    Article  CAS  Google Scholar 

  31. [31]

    Khromykha, A.A., Harveya, T.J., Abediniab, M., Westaway, E.G. 1996. Expression and purification of the seven nonstructural proteins of the flavivirus Kunjin in the E. coli and the baculovirus expression systems. J Virol Methods 61, 47–58.

    Article  Google Scholar 

  32. [32]

    Laskowski, R.A., MacArthur, M.W., Moss, D.S., Thornton, J.M. 1993. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Crystallogr 26, 283–291.

    Article  CAS  Google Scholar 

  33. [33]

    Lee, E., Lobigs, M. 2000. Substitutions at the putative receptor binding site of an encephalitic flavivirus alter virulence and host cell tropism and reveal a role for glycosaminoglycans in entry. J Virol 74, 8867–8875.

    PubMed  Article  CAS  Google Scholar 

  34. [34]

    Li, Z., Khaliq, M., Zhou, Z., Post, C.B., Kuhn, R.J., Cushman, M. 2008. Design, synthesis, and biological evaluation of antiviral agents targeting flavivirus envelope proteins. J Med Chem 51, 4660–4671.

    PubMed  Article  CAS  Google Scholar 

  35. [35]

    Lobigs, M., Usha, R., Nestorowicz, A., Marshall, I.D., Weir, R.C., Dalgarno, L. 1990. Host cell selection of Murray Valley encephalitis virus variants altered at an RGD sequence in the envelope protein and in mouse virulence. Virology 176, 587–595.

    PubMed  Article  CAS  Google Scholar 

  36. [36]

    Maestro v9.0, 2009. Schrodinger, LLC, Portland, OR.

  37. [37]

    Mandl, C.W., Allison, S.L., Holzmann, H., Meixner, T., Heinz, F.X. 2000. Attenuation of tick-borne encephalitis virus by structure based site-specific mutagenesis of a putative flavivirus receptor binding site. J Virol 74, 9601–9609.

    PubMed  Article  CAS  Google Scholar 

  38. [38]

    Modis, Y., Ogata, S., Clements, D., Harrison, S.C. 2003. A ligand-binding pocket in the Dengue virus envelope glycoprotein. Proc Natl Acad Sci USA 100, 6986–6991.

    PubMed  Article  CAS  Google Scholar 

  39. [39]

    Modis, Y., Ogata, S., Clements, D., Harrison, S.C. 2004. Structure of the Dengue virus envelope protein after membrane fusion. Nature 427, 313–319.

    PubMed  Article  CAS  Google Scholar 

  40. [40]

    Monath, T.P. 1986. Pathology of the flaviviruses. In: Schlesinger, S., Schlesinger, M.J. (eds) The Togaviridae and Flaviviridae. Academic Press Inc, New York, 375–440.

    Google Scholar 

  41. [41]

    Nayak, V., Dessau, M., Kucera, K., Anthony, K., Ledizet, M., Modis, Y. 2009. Crystal structure of Dengue virus type 1 envelope protein in the postfusion conformation and its implications for membrane fusion. J Virol 83, 4338–4344.

    PubMed  Article  CAS  Google Scholar 

  42. [42]

    Oldstone, M.B.A. 2000. Viruses, Plagues, and History. Oxford University Press, UK.

    Google Scholar 

  43. [43]

    op de Beeck, A., Rouillé, Y., Caron, M., Duvet, S., Dubuisson, J. 2004. The transmembrane domains of the prM and E Proteins of yellow fever virus are endoplasmic reticulum localization signals. J Virol 78, 12591–12602.

    Article  Google Scholar 

  44. [44]

    Rey, F.A., Heinz, F.X., Mandl, C., Kunz, C., Harrison, S.C. 1995. The envelope glycoprotein from tick-borne encephalitis virus at 2 A0 resolution. Nature 375, 291–298.

    PubMed  Article  CAS  Google Scholar 

  45. [45]

    Rice, C.M. 1996. Flaviviridae: The viruses and their replication. In: Fields, B.N., Knipe, D.M., Howley, P.M. (eds) Lippincott-Raven Publishers, Philadelphia, 931–960.

    Google Scholar 

  46. [46]

    Rice, C.M., Strauss, J.H. 1986. Structure of the flavivirus genome. In: Schlesinger, S., Schlesinger, M.J. (eds), The Togaviridae and Flaviviridae. Academic Press Inc, New York, 279–326.

    Google Scholar 

  47. [47]

    Roehrig, J.T. 1997. Immunochemistry of the Dengue viruses. In: Gubler, D.J., Kuno, G. (eds), Dengue and Dengue Hemorrhagic Fever. CAB International, New York, 199–219.

    Google Scholar 

  48. [48]

    Sali, A., Blundell, T.L. 1993. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234, 779–815.

    PubMed  Article  CAS  Google Scholar 

  49. [49]

    Schmaljohn, A.L., McClain, D. 1996. Alphaviruses (togaviridae) and flaviviruses (flaviviridae). In: Baron, S. (ed), Medical Microbiology. Univ of Texas Medical Branch.

  50. [50]

    Sekhar, P.N., Reddy, L.A., De, Maeyer, M., Kumar, K.P., Srinivasulu, Y.S., Sunitha, M.S., Sphoorthi, I.S., Jayasree, G., Rao, A.M., Kothekar, V.S., Narayana, P.V., Kishor, P.B. 2009. Genome wide analysis and comparative docking studies of new diaryl furan derivatives against human cyclooxygenase-2, lipoxygenase, thromboxane synthase and prostacyclin synthase enzymes involved in inflammatory pathway. J Mol Graph Model 28, 313–329.

    PubMed  Article  CAS  Google Scholar 

  51. [51]

    Speight, G., Coia, G., Parker, M.D., Westaway, E.G. 1988. Gene mapping and positive identification of the non-structural proteins NS2A, NS2B, NS3, NS4B and NS5 of the flavivirus Kunjin and their cleavage sites. J Gen Virol 69, 23–34.

    PubMed  Article  CAS  Google Scholar 

  52. [52]

    Thompson, J.D., Gibson, T.J., Plewniak, F., Jeanmougin, F., Higgins, D.G. 1997. The CLUSTALX windows interface: Flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25, 4876–4882.

    PubMed  Article  CAS  Google Scholar 

  53. [53]

    Umamaheswari, A., Pradhan, D., Hemanthkumar, M. 2010. Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase. J Chem Biol (in press). doi: 10.1007/s12154-010-0040-8.

  54. [54]

    Wallner, B., Elofsson, A. 2003. Can correct protein models be identified? Protein Sci 12, 1073–1086.

    PubMed  Article  CAS  Google Scholar 

  55. [55]

    Wiederstein, M., Sippl, M.J. 2007. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35, 407–410.

    Article  Google Scholar 

  56. [56]

    Zhou, Z., Khaliq, M., Suk, J.E., Patkar, C., Li, L., Kuhn, R.J., Post, C.B. 2008. Antiviral compounds discovered by virtual screening of small-molecule libraries against dengue virus E protein. ACS Chem Biol 3, 765–775.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Amineni Umamaheswari.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Umamaheswari, A., Kumar, M.M., Pradhan, D. et al. Docking studies towards exploring antiviral compounds against envelope protein of yellow fever virus. Interdiscip Sci Comput Life Sci 3, 64–77 (2011).

Download citation

Key words

  • yellow fever virus
  • envelope protein
  • homology modeling
  • virtual screening
  • antiviral compound