Journal of Computer-Aided Molecular Design

, Volume 10, Issue 3, pp 233–246 | Cite as

A structural and energetics analysis of the binding of a series of N-acetylneuraminic-acid-based inhibitors to influenza virus sialidase

  • Neil R. Taylor
  • Mark von Itzstein
Research Paper


A molecular dynamics/energy-minimisation protocol has been used to analyse the structural and energetic effects of functional group substitution on the binding of a series of C4-modified 2-deoxy-2,3-didehydro-N-acetylneuraminic acid inhibitors to influenza virus sialidase. Based on the crystal structure of sialidase, a conformational searching protocol, incorporating multiple randomisation steps in a molecular dynamics simulation was used to generate a range of minimum-energy structures. The calculations were useful for predicting the number, location, and orientation of structural water molecules within protein-ligand complexes. Relative binding energies were calculated for the series of complexes using several empirical molecular modelling approaches. Energies were computed using molecular-mechanics-derived interactions as the sum of pairwise atomic nonbonded energies, and in a more rigorous manner including solvation effects as the change in total electrostatic energy of complexation, using a continuum-electrostatics (CE) approach. The CE approach exhibited the superior correlation with observed affinities. Both methods showed definite trends in observed and calculated binding affinities; in both cases inhibitors with a positively charged C4 substituent formed the tightest binding to the enzyme, as observed experimentally.


Calculated binding energies Molecular mechanics Continuum electrostatics Sialidase Influenza 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    vonItzstein, M., Wu, W.-Y., Kok, G.B., Pegg, M.S., Dyason, J.C., Jin, B., Van Phan, T., Smythe, M.L., White, H.F., Oliver, S.W., Colman, P.M., Varghese, J.N., Ryan, D.M., Woods, J.M., Bethell, R.C., Hotham, V.J., Cameron, J.M. and Penn, C.R., Nature, 363 (1993) 418.Google Scholar
  2. 2.
    Holzer, C.T., vonItzstein, M., Jin, B., Pegg, M.S., Stewart, W.P. and Wu, W.-Y., Glycoconjugate J., 10 (1993) 40.Google Scholar
  3. 3.
    vonItzstein, M., Wu, W.-Y. and Jin, B., Carbohydr. Res., 259 (1994a) 301.Google Scholar
  4. 4.
    Chong, A.K., Pegg, M.S. and vonItzstein, M., Biochem. Int., 24 (1991a) 165.Google Scholar
  5. 5.
    Chong, A.K., Pegg, M.S., Taylor, N.R. and vonItzstein, M., Eur. J. Biochem., 207 (1992) 335.Google Scholar
  6. 6.
    Taylor, N.R. and vonItzstein, M., J. Med. Chem., 37 (1994) 616.Google Scholar
  7. 7.
    Colman, P.M., Pept. Protein Rev., 4 (1984) 215.Google Scholar
  8. 8.
    Chong, A.K., Pegg, M.S. and vonItzstein, M., Biochim. Biophys. Acta., 1077 (1991b) 65.Google Scholar
  9. 9.
    Varghese, J.N., McKimm-Breschkin, J., Caldwell, J.B., Kortt, A.A. and Colman, P.M., Proteins, 14 (1992) 327.Google Scholar
  10. 10.
    vonItzstein, M., Dyason, J.C., Oliver, S.W., White, H.F., Wu, W.-Y., Kok, G.B. and Pegg, M.S., J. Med. Chem., 39 (1996) 388.Google Scholar
  11. 11.
    Varghese, J.N. and Colman, P.M., J. Mol. Biol., 221 (1991) 473.Google Scholar
  12. 12.
    Howard, A.E. and Kollman, P.A., J. Med. Chem., 31 (1988) 1660.Google Scholar
  13. 13.
    Leach, A.R., In Lipkowitz, K.B. and Boyd, D.B. (Eds.) Reviews in Computational Chemistry II, VCH, New York, NY, 1991, p. 1.Google Scholar
  14. 14.
    Wong, C.F. and McCammon, J.A., J. Am. Chem. Soc., 108 (1986) 3830.Google Scholar
  15. 15.
    VanGunsteren, W.F. and Berendsen, H.J.C., J. Comput.-Aided Mol. Design, 1 (1987) 171.Google Scholar
  16. 16.
    McCammon, J.A., Science, 238 (1987) 486.Google Scholar
  17. 17.
    Lee, F.S., Chu, Z.-T., Bolger, M.B. and Warshel, A., Protein Eng., 5 (1992) 215.Google Scholar
  18. 18.
    Andrews, P.R., Craik, D.J. and Martin, J.L., J. Med. Chem., 27 (1984) 1648.Google Scholar
  19. 19.
    Novotny, J., Bruccoleri, R.E. and Saul, F.A., Biochem., 28 (1989) 4735.Google Scholar
  20. 20.
    Williams, D.H., Aldrichim. Acta, 24 (1991) 71.Google Scholar
  21. 21.
    Horton, N. and Lewis, M., Protein Sci., 1 (1992) 169.Google Scholar
  22. 22.
    Searle, M.S. and Williams, D.H., J. Am. Chem. Soc., 114 (1992) 10690.Google Scholar
  23. 23.
    Searle, M.S., Williams, D.H. and Gerhard, U., J. Am. Chem. Soc., 114 (1992) 10697.Google Scholar
  24. 24.
    Murphy, K.P., Xie, D., Garcia, C., Amzel, L.M. and Freire, E., Proteins, 15 (1993) 113.Google Scholar
  25. 25.
    Shoichet, B.K., Bodian, D.L. and Kuntz, I.D., J. Comp. Chem., 13 (1994) 380.Google Scholar
  26. 26.
    Lawrence, M.C. and Davis, P.C., Proteins, 12 (1992) 31.Google Scholar
  27. 27.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 8 (1994) 243.Google Scholar
  28. 28.
    Miller, M.D., Kearsley, S.K., Underwood, D.J. and Sheridan, R.P., J. Comput.-Aided Mol. Design, 8 (1994) 153.Google Scholar
  29. 29.
    Gilson, M.K. and Honig, B., Nature, 330 (1987) 84.Google Scholar
  30. 30.
    Gilson, M.K., Sharp, K. and Honig, B., J. Comp. Chem., 9 (1988) 327.Google Scholar
  31. 31.
    Gilson, M.K. and Honig, B., Proteins, 4 (1988) 7.Google Scholar
  32. 32.
    Alkorta, I., Villar, H.O. and Perez, J.J., J. Comp. Chem., 14 (1993) 620.Google Scholar
  33. 33.
    Sitkoff, D., Sharp, K.A. and Honig, B., J. Phys. Chem., 98 (1994) 1978.Google Scholar
  34. 34.
    Dauber-Osguthorpe, P., Roberts, V.A., Osguthorpe, D.J., Wolff, J., Genest, M. and Hagler, A.T., Proteins, 4 (1988) 31.Google Scholar
  35. 35.
    Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Ghio, C., Alagona, G., Profeta Jr, S. and Weiner, P., J. Am. Chem. Soc., 106 (1984) 765.Google Scholar
  36. 36.
    Pegg, M.S. and vonItzstein, M., Biochem. Mol. Biol. Int., 32 (1994) 851.Google Scholar
  37. 37.
    Burmeister, W.P., Ruigrok, R.W.H. and Cusack, S., EMBO. J., 11 (1991) 49.Google Scholar
  38. 38.
    Smith, P.E., Brunne, R.M., Mark, A.E. and VanGunsteren, W.F., J. Phys. Chem., 97 (1993) 711.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1996

Authors and Affiliations

  • Neil R. Taylor
    • 1
  • Mark von Itzstein
    • 1
  1. 1.Department of Medicinal Chemistry, Victorian College of PharmacyMonash UniversityParkvilleAustralia

Personalised recommendations