Skip to main content
Springer Nature Link
Log in

Current methods for site-directed structure generation

  • Review
  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Summary

There has been a rapid growth of interest in techniques for site-directed drug design, fuelled by the increasing availability of structural models of proteins of therapeutic importance, and by studies reported in the literature showing that potent chemical leads can be obtained by these techniques. Structure generation programs offer the prospect of discovering highly original lead structures from novel chemical families. Due to the fact that this technique is more-or-less still in its infancy, there are no case studies available that demonstrate the use of structure generation programs for site-directed drug design. Such programs were first proposed in 1986, and became commercially available in early 1992. They have shown their ability to reproduce, or suggest reasonable alternatives for, ligands in well-defined binding sites. This brief review will discuss the recent advances that have been made in the field of site-directed structure generation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dean, P.M., Molecular Foundations of Drug-Receptor Interaction, Cambridge University Press, Cambridge, 1987.

    Google Scholar 

  2. Lam, P.Y.S., Jadhav, P.K., Eyermann, C.J., Hodge, C.N., Ru, Y., Bacheler, L.T., Meek, J.L., Otto, M.J., Rayner, M.M., Wong, Y.N., Chang, C.-H., Weber, P.C., Jackson, D.A., Sharpe, T.R. and Erickson-Viitanen, S., Science, 263 (1994) 380.

    Google Scholar 

  3. Appelt, K., Bacquet, R.J., Bartlett, C.A., Booth, C.L.J., Freer, S.T., Fuhry, M.A.M., Gehring, M.R., Herrmann, S.M., Howland, E.F., Janson, C.A., Jones, T.A., Kan, C.-C., Kathadekar, V., Lewis, K.K., Marzoni, G.P., Matthews, D.A., Mohr, C., Moomaw, E.W., Morse, C.A., Oatley, S.J., Ogden, R.C., Reddy, M.R., Reich, S.H., Schoettlin, W.S., Smith, W.W., Varney, M.D., Villafranca, J.E., Ward, R.W., Webber, S., Welsh, K.M. and White, J., J. Med. Chem., 34 (1991) 1925.

    Google Scholar 

  4. Shoichet, B.K., Stroud, R.M., Santi, D.V., Kuntz, I.D. and Perry, K.M., Science, 259 (1993) 1445.

    Google Scholar 

  5. Kuntz, I.D., Science, 257 (1992) 1078.

    Google Scholar 

  6. Martin, Y.C., J. Med. Chem., 35 (1992) 2145.

    Google Scholar 

  7. Goodford, P.J., J. Med. Chem., 28 (1985) 849.

    Google Scholar 

  8. Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Ghio, C., Alagona, G., Profeta, S. and Weiner, P., J. Am. Chem. Soc., 106 (1984) 765.

    Google Scholar 

  9. Brooks, B.R., Bruccoleri, B.E., Olafson, B., States, D.J., Swaminathan, S. and Karplus, M., J. Comput. Chem., 4 (1983) 187.

    Google Scholar 

  10. Murray-Rust, P. and Glusker, J.P., J. Am. Chem. Soc., 106 (1984) 1018.

    Google Scholar 

  11. Taylor, R. and Kennard, O., Acc. Chem. Res., 17 (1984) 320.

    Google Scholar 

  12. Danziger, D.J. and Dean, P.M., Proc. R. Soc. London, Ser. B, 236 (1989) 115.

    Google Scholar 

  13. Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.

    Google Scholar 

  14. Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 593.

    Google Scholar 

  15. DesJarlais, R.L., Sheridan, R.P., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem., 29 (1986) 2149.

    Google Scholar 

  16. Leach, A.R., Prout, K. and Dolata, D.P., J. Comput.-Aided Mol. Design, 2 (1988) 107.

    Google Scholar 

  17. Moon, J.B. and Howe, W.J., Protein Struct. Funct. Genet., 11 (1991) 314.

    Google Scholar 

  18. Rotstein, S.H. and Murcko, M.A., J. Med. Chem., 36 (1993) 1700.

    Google Scholar 

  19. Rotstein, S.H. and Murcko, M.A., J. Comput.-Aided Mol. Design, 7 (1993) 23.

    Google Scholar 

  20. Nishibata, Y. and Itai, A., J. Med. Chem., 36 (1993) 2921.

    Google Scholar 

  21. Bohacek, R. and McMillen, C., Abstract OC-08.4, XIIth International Symposium on Medicinal Chemistry, Basel, 1992.

  22. Nilakantan, R., Bauman, N. and Venkataraghavan, R., J. Chem. Inf. Comput. Sci., 31 (1991) 527.

    Google Scholar 

  23. Leach, A.R. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 730.

    Google Scholar 

  24. Lewis, R.A. and Dean, P.M., Proc. R. Soc. London, Ser. B, 236 (1989) 125.

    Google Scholar 

  25. Lewis, R.A. and Dean, P.M., Proc. R. Soc. London, Ser. B, 236 (1989) 141.

    Google Scholar 

  26. Lewis, R.A., J. Comput.-Aided Mol. Design, 4 (1990) 205.

    Google Scholar 

  27. Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.

    Google Scholar 

  28. Lewis, R.A., In Karjalainen, E.J. (Ed.) Proceedings of Scientific Computing and Automation, Elsevier, Amsterdam, 1990, pp. 117–132.

    Google Scholar 

  29. Lewis, R.A., Roe, D.C., Huang, C., Ferrin, T.E., Langridge, R. and Kuntz, I.D., J. Mol. Graphics, 10 (1992) 66.

    Google Scholar 

  30. Gillet, V., Johnson, A.P., Mata, P., Sike, S. and Williams, P., J. Comput.-Aided Mol. Design, 7 (1993) 127.

    Google Scholar 

  31. Miranker, A. and Karplus, M., Protein Struct. Funct. Genet., 11 (1991) 29.

    Google Scholar 

  32. Pearlman, D.A. and Mureko, M.A., J. Comput. Chem., 14 (1993) 1184.

    Google Scholar 

  33. biosym Technologies Inc., San Diego, CA.

  34. Bartlett, P.A., Shea, J.T., Telfer, S.J. and Waterman, S., In Roberts, S.M. (Ed.) Molecular Recognition: Chemical and Biological Problems, Royal Society of Chemistry, London, 1989, pp. 182–196.

    Google Scholar 

  35. Tschinke, V. and Cohen, N.C., J. Med. Chem., 36 (1993) 3863.

    Google Scholar 

  36. Eisen, M.B. and Hubbard, R.E., personal communication.

  37. Allen, F.H., Bellard, S.A., Brice, M.D., Cartwright, B.A., Doubleday, A., Higgs, H., Hummelink, T., Hummelink-Peters, B.G., Kennard, O., Motherwell, W.D.S., Rodgers, J.R. and Watson, D.G., Acta Crystallogr., B 35 (1979) 2331.

    Google Scholar 

  38. Ho, C.M. and Marshall, G.R., J. Comput.-Aided Mol. Design, 7 (1963) 623.

    Google Scholar 

  39. Lewis, R.A., J. Mol. Graphics, 10 (1992) 66.

    Google Scholar 

  40. Gō, N. and Scheraga, H.A., Macromolecules, 3 (1970) 178.

    Google Scholar 

  41. Bruccoleri, R.E. and Karplus, M., Macromolecules, 18 (1985) 2767.

    Google Scholar 

  42. Leach, A.R. and Kilvington, S.R., J. Comput.-Aided Mol. Design, 8 (1994) 283.

    Google Scholar 

  43. Shenkin, P.S., Yarmush, D.L., Fine, R.M., Wang, H. and Levinthal, C., Biopolymers, 26 (1987) 2053.

    Google Scholar 

  44. Weininger, D., Dixon, J.S. and Blaney, J.M., (1993) Daylight Chemical Information Systems Inc., Santa Fe, NM.

  45. Cramer, R.D. and DePriest, S., implemented in the Sybyl program (1993), Tripos Associates, St. Louis, MO.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dagenham Research Centre, Rhóne-Poulenc Rorer Ltd., RM10 7XS, Dagenham, Essex, U.K.

    Richard A. Lewis

  2. Department of Chemistry, University of Southampton, Highfield, SO9 5NH, Southampton, U.K.

    Andrew R. Leach

Authors
  1. Richard A. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew R. Leach
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lewis, R.A., Leach, A.R. Current methods for site-directed structure generation. J Computer-Aided Mol Des 8, 467–475 (1994). https://doi.org/10.1007/BF00125381

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00125381

Key words