Skip to main content
SpringerLink
Log in

Structure-based drug design (SBDD): Every structure tells a story...

  • Perspectives Part IV. Empirical Support For Theoretical Studies
  • Published:
Perspectives in Drug Discovery and Design

Summary

In this article we report how protein-ligand X-ray structures can be used to identify and develop new drug candidates. The structure-based drug design approach (SBDD) is described, illustrating the way crystallographic information is utilized in an iterative manner to identify and optimize novel lead compounds, thereby accelerating the overall drug discovery process. The requirements for the effective use of SBDD and its implementation, drawing upon case histories from our Thymidylate Synthase (TS) research program, are described.

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

Access this article

Log in via an institution

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. Beddell, C.R., Goodford, P.J., Kneen, G., White, R.D., Wilkinson, S. and Wootton, R., Br. J. Pharmacol., 82 (1984) 397.

    Google Scholar 

  2. Kuyper, L.F., Roth, B., Baccanari, D.P., Ferone, R., Beddell, C.R., Champness, J.N., Stammers, D.K., Dann, J.G., Norrington, F.E., Baker, D.J. and Goodford, P.J., J. Med. Chem., 28 (1985) 303.

    Google Scholar 

  3. Ripka, W.C., Sipio, W.J. and Blaney, J.M., J. Heterocyclic Chem., 24 (1987) S-95.

  4. Baldwin, J.J., Ponticello, G.S., Anderson, P.S., Christy, M.E., Murcko, M.A., Randall, W.C., Schwam, H., Surgrue, M.F., Springer, J.P., Gautheron, P., Grove, J., Mallorga, P., Viader, M.P., McKeever, B.M. and Navia, M.A., J. Med. Chem. 32 (1989) 2510.

    Google Scholar 

  5. Ealick, S.E., Babu, Y.S., Bugg, C.E., Erion, M.D., Guida, W.C., Montgomery, J.A. and Secrist III, J.A., Proc. Natl. Acad. Sci. USA, 88 (1991) 11540.

    Google Scholar 

  6. Montgomery, J.A., Niwas, S., Rose, J.D., Secrist III, J.A., Babu, Y.S., Bugg, C.E., Erion, M.D., Guida, W.C. and Ealick, S.E., J. Med. Chem., 36 (1993) 55.

    Google Scholar 

  7. Von Itzstein, M., Wu, W.-U., Kok, G.B., Pegg, M.S., Dyason, J.C., Jin, B., Phan, T.V., 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 

  8. Thompson, W.J., Fitzgerald, P.M.D., Holloway, M.K., Emini, E.A., Darke, P.L., McKeever, B.M., Schleif, W.A., Quintero, J.C., Zugay, J.A., Tucker, T.J., Schwering, J.E., Homnick, C.F., Nunberg, J., Springer, J.P. and Huff, J.R., J. Med. Chem., 35 (1992) 1685.

    Google Scholar 

  9. Roth, M., Lewit-Bentley, A., Michel, H., Deisenhofer, J., Huber, R. and Oesterhelt, D., Nature, 340 (1989) 659.

    Google Scholar 

  10. Weiss, M.S. and Schulz, G.E., J. Mol. Biol., 227 (1992) 493.

    PubMed  Google Scholar 

  11. Connolly, M.L., Science, 221 (1983) 709.

    Google Scholar 

  12. DelPhi is a product of Biosym Technologies. See also: Gilson, M. and Honig, B., Proteins, 4 (1988) 7.

    Google Scholar 

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

    Google Scholar 

  14. Jones, T.R., Calvert, A.H., Jackman, A.L., Brown, S.J., Jones, M. and Harrap, K.R., Eur. J. Cancer, 17 (1981) 11.

    Google Scholar 

  15. Matthews, D.A., Appelt, K., Oatley, S.J. and Xuong, N.H., J. Mol. Biol., 214 (1990) 923.

    Google Scholar 

  16. Webber, S.E., unpublished results.

  17. Matthews, D.A., Bolin, J.T., Burridge, J.M., Filman, D.J., Volz, K.W., Kaufman, B.T., Beddell, C.R., Champness J.N., Stammers, D.K., and Kraut, J., J. Biol. Chem., 260 (1985) 381.

    Google Scholar 

  18. Schlichting, I., Almo, S.C., Rapp, G., Wilson, K., Petratos, K., Lentfer, A., Wittinghofer, A., Kabsch, W., Pai, E.F., Petsko, G.A. and Goody, R.S., Nature, 345 (1990) 309.

    Google Scholar 

  19. Arnone, A., Benesch, R.E. and Benesch, R., J. Mol. Biol., 115 (1977) 627.

    Google Scholar 

  20. Brayer, G.D., Delbaere, L.J.T., James, M.N.G., Bauer, C.-A. and Thompson, R.C., Proc. Natl. Acad. Sci. USA, 76 (1979) 96.

    Google Scholar 

  21. Matthews, D.A., Villafranca, J.E., Janson, C.A., Smith, W.W. and Welsh, K. and Freer, S., J. Mol. Biol., 214 (1990) 937.

    Google Scholar 

  22. An example is the Monte Carlo method for conformational searching in the program Macromodel (Interactive Molecular Modeling System, Version 4.0, Department of Chemistry, Columbia University, New York, NY).

  23. McNamara, D.J., Berman, E.M., Fry, D.W. and Werbel, L.M., J. Med. Chem., 33 (1990) 2045.

    Google Scholar 

  24. Jones, T.R., Varney, M.D., Webber, S.E., Welsh, K.M., Webber, S., Matthews, D.A., Appelt, K., Smith, W.W., Janson, C., Bacquet, R., Lewis, K.K., Marzoni, G.P., Kathardekar, V., Howland, E., Booth, C., Hermann, S., Ward, R., Sharp, J., Moomaw, E., Bartlett, C. and Morse, C., Proc. Am. Assoc. Cancer Res., 31 (1990) 340.

    Google Scholar 

  25. Newall, D.R., Siddik, Z.H., Calvert, A.H., Jackman, A.L., Alison, D.L., McGhee, K.G. and Harrap, K.R., Proc. Am. Assoc. Cancer Res., 23 (1982) 181.

    Google Scholar 

  26. Appelt, K. and Bacquet, R.J., Bartlett, C.A., Booth, C.L.J., Freer, S.T., Fuhry, M.M., Gehring, M.R., Herrmann, S.M., Howland, E.F., Janson, C.A., Jones, T.R., Kan, C., Kathardekar, 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., Webber, S.E., Welsh, K.M. and White, J., J. Med. Chem., 34 (1991) 1925.

    Google Scholar 

  27. Hughes, L.R., Jackman, A.L., Oldfield, J., Smith, R.C., Burrows, K.D., Marsham, P.R., Bishop, J.A.M., Jones, T.R., O'Connor, B.M. and Calvert, A.H., J. Med. Chem., 33 (1990) 3060.

    Google Scholar 

  28. Warshel, A. and Acvist, J., Annu. Rev. Biophys. Biophys. Chem., 20 (1991) 267.

    Google Scholar 

  29. Webber, S.E. and Bleckman, T.M., Attard, J., Deal, J.G., Kathardekar, V., Welsh, K.M., Webber, S., Janson, C.A., Matthews, D.A., Smith, W.W., Freer, S.T., Jordan, S.R., Bacquet, R.J., Howland, E.F., Booth, C.L.J., Ward, R.W., Hermann, S.M., White, J., Morse, C.A., Hilliard, J.A. and Bartlett, C.A., J. Med. Chem., 36 (1993) 733.

    Google Scholar 

  30. Reich, S.H., Fuhry, M.M., Nguyen, D., Pino, M.J., Welsh, K.M., Webber, S., Janson, C., Jordan, S.R., Matthews, D.A., Smith, W.W., Bartlett, C.A., Booth, C.L.J., Herrmann, S.M., Howland, E.F., Morse, C.A., Ward, R.W. and White, J., J. Med. Chem., 35 (1992) 847.

    Google Scholar 

  31. Varney, M.D., Marzoni, G.P., Palmer, C.L., Deal, J.G., Webber, S., Welsh, K.M., Bacquet, R.J., Bartlett, C.A., Morse, C.A., Booth, C.L.J., Herrmann, S.M., Howland, E.F., Ward, R.W. and White, J., J. Med. Chem. 35 (1992) 663.

    Google Scholar 

  32. Reddy, M.R., Bacquet, R.J. and Varney, M.D., J. Chim. Phys., 88 (1991) 2605.

    Google Scholar 

  33. MCDNLG (Monte Carlo De Novo Ligand Generator): Gelhaar, D., Sherman, C., Moerder, K., Zichi, D., Ogden, R. and Freer, S., Agouron Pharmaceuticals, Inc., unpublished results.

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

    Google Scholar 

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

    Google Scholar 

  36. LUDI: Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.

    Google Scholar 

  37. LEGEND: Nishibata, Y. and Itai, A., Tetrahedron, 47 (1991) 8985.

    Google Scholar 

  38. Leapfrog: Tripos Associates, Inc., St. Louis, MO, 1993.

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

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, 92121, San Diego, CA, USA

    Siegfried H. Reich & Stephen E. Webber

Authors
  1. Siegfried H. Reich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen E. Webber
    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

Reich, S.H., Webber, S.E. Structure-based drug design (SBDD): Every structure tells a story.... Perspectives in Drug Discovery and Design 1, 371–390 (1993). https://doi.org/10.1007/BF02174536

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02174536

Key words

Search

Navigation