Journal of Computer-Aided Molecular Design

, Volume 9, Issue 3, pp 213–225 | Cite as

PRO_LIGAND: An approach to de novo molecular design. 4. Application to the design of peptides

  • David Frenkel
  • David E. Clark
  • Jin Li
  • Christopher W. Murray
  • Barry Robson
  • Bohdan Waszkowycz
  • David R. Westhead
Research Papers

Summary

In some instances, peptides can play an important role in the discovery of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or complementary to a specified target. The approach uses single amino acid residues, selected from preconstructed libraries of different residues and conformations, and places them on top of predefined target interaction sites. This approach is a well-tested methodology for the design of organics but has not been used for peptides before. Peptides represent a difficulty because of their great conformational flexibility and a study of the advantages and disavantages of this simple approach is an important step in the development of design tools. After a description of our general approach, a more detailed discussion of its adaptation to peptides is given. The method is then applied to the design of peptide-based inhibitors to HIV-1 protease and the design of structural mimics of the surface region of lysozyme. The results are encouraging and point the way towards further development of interaction site-based approaches for peptide design.

Keywords

Computer-aided molecular design De novo peptide design HIV-1 protease inhibitors Lysozyme epitopes Synthetic vaccine design 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Walkinshaw, M.D., Med. Res. Rev., 12 (1992) 317.Google Scholar
  2. 2.
    Ealick, S.E. and Armstrong, S.R., Curr. Opin. Struct. Biol., 3 (1993) 861.Google Scholar
  3. 3.
    Fesik, S.W., J. Biomol. NMR, 3 (1993) 261.Google Scholar
  4. 4.
    Zuiderweg, E.R.P., Van, Doren, S.R., Kurochkin, A.V., Neubig, R.R. and Majumdar, A., Perspect. Drug Discov. Design, 1 (1993) 391.Google Scholar
  5. 5.
    Reich, S.H. and Webber, S.E., Perspect. Drug Discov. Design, 1 (1993) 371.Google Scholar
  6. 6.
    Greer, J., Erickson, J.W., Baldwin, J.J. and Varney, M.D., J. Med. Chem., 37 (1994) 1035.Google Scholar
  7. 7.
    Whittle, P.J. and Blundell, T.L., Annu. Rev. Biophys. Biomol. Struct., 23 (1994) 349.Google Scholar
  8. 8.
    Verlinde, C.L.M.J. and Hol, W.G.J., Structure, 2 (1994) 577.Google Scholar
  9. 9.
    Colman, P.M., Curr. Opin. Struct. Biol., 4 (1994) 868.Google Scholar
  10. 10.
    Mayer, D., Naylor, C.B., Motoc, I. and Marshall, G.R., J. Comput.-Aided Mol. Design, 1 (1987) 3.Google Scholar
  11. 11.
    Sheridan, R.P., Nilakantan, R., Dixon, J.S. and Venkataraghavan, R., J. Med. Chem., 29 (1986) 899.Google Scholar
  12. 12.
    Cramer, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.Google Scholar
  13. 13.
    Martin, Y.C., Bures, M.G., Danaher, E.A., DeLazzar, J., Lico, I. and Pavlik, P.A., J. Comput-Aided Mol. Design, 7 (1993) 83.Google Scholar
  14. 14.
    Moon, J.B. and Howe, W.J., Protein Struct. Funct. Genet., 11 (1991) 314.Google Scholar
  15. 15.
    Moon, J.B. and Howe, W.J., In Wermuth, C.G. (Ed.) Trends in QSAR and Molecular Modelling 92 (Proceedings of the 9th European Symposium on Structure-Activity Relationships: QSAR and Molecular Modelling), ESCOM, Leiden, 1993, pp. 11–19.Google Scholar
  16. 16.
    Miranker, A. and Karplus, M., Protein Struct. Funct. Genet., 11 (1991) 29.Google Scholar
  17. 17.
    Caflisch, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.Google Scholar
  18. 18.
    Nishibata, Y. and Itai, A., Tetrahedron, 47 (1991) 8985.Google Scholar
  19. 19.
    Nishibata, Y. and Itai, A., J. Med. Chem., 36 (1993) 2921.Google Scholar
  20. 20.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.Google Scholar
  21. 21.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 593.Google Scholar
  22. 22.
    Böhm, H.-J., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, 1993, pp. 386–405.Google Scholar
  23. 23.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 8 (1994) 243.Google Scholar
  24. 24.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 8 (1994) 623.Google Scholar
  25. 25.
    Lewis, R.A., Roe, D.C., Huang, C., Ferrin, T.E., Langridge, R. and Kuntz, I.D., J. Mol. Graph., 10 (1992) 66.Google Scholar
  26. 26.
    Rotstein, S.H. and Murcko, M.A., J. Comput.-Aided Mol. Design, 7 (1993) 23.Google Scholar
  27. 27.
    Rotstein, S.H. and Murcko, M.A., J. Med. Chem., 36 (1993) 1700.Google Scholar
  28. 28.
    Gillet, V.J., Johnson, A.P., Mata, P., Sike, S. and Williams, P., J. Comput.-Aided Mol. Design, 7 (1993) 127.Google Scholar
  29. 29.
    Gillet, V.J., Newell, W., Mata, P., Myatt, G., Sike, S., Zsoldos, Z. and Johnson, A.P., J. Chem. Inf. Comput. Sci., 34 (1994) 207.Google Scholar
  30. 30.
    Pearlman, D.A. and Murcko, M.A., J. Comput. Chem., 14 (1993) 1184.Google Scholar
  31. 31.
    Tschinke, V. and Cohen, N.C., J. Med. Chem., 36 (1993) 3863.Google Scholar
  32. 32.
    Ho, C.W.M. and Marshall, G.R., J. Comput.-Aided Mol. Design, 7 (1993) 623.Google Scholar
  33. 33.
    Leach, A.R. and Lewis, R.A., J. Comput. Chem., 15 (1994) 233.Google Scholar
  34. 34.
    Leach, A.R. and Kilvington, S.R., J. Comput.-Aided Mol. Design, 8 (1994) 283.Google Scholar
  35. 35.
    Eisen, M.B., Wiley, D.C., Karplus, M. and Hubbard, R.E., Protein Struct. Funct. Genet., 19 (1994) 199.Google Scholar
  36. 36.
    Bohacek, R.S. and McMartin, C., J. Am. Chem. Soc., 116 (1994) 5560.Google Scholar
  37. 37.
    Cohen, A.A. and Shatzmiller, S.E., J. Mol. Graph., 11 (1993) 166.Google Scholar
  38. 38.
    Cohen, A.A. and Shatzmiller, S.E., J. Comput. Chem., 15 (1994) 1393.Google Scholar
  39. 39.
    Clark, D.E., Frenkel, D., Levy, S.A., Li, J., Murray, C.W., Robson, B., Waszkowycz, B. and Westhead, D.R., J. Comput.-Aided Mol. Design, 9 (1995) 13.Google Scholar
  40. 40.
    Waszkowycz, B., Clark, D.E., Frenkel, D., Li, J., Murray, C.W., Robson, B. and Westhead, D.R., J. Med. Chem., 37 (1994) 3994.Google Scholar
  41. 41.
    Westhead, D.R., Clark, D.E., Frenkel, D., Li, J., Murray, C.W., Robson, B. and Waszkowycz, B., J. Comput.-Aided Mol. Design, 9, (1995) 139.Google Scholar
  42. 42.
    Lewis, R.A. and Leach, A.R., J. Comput.-Aided Mol. Design, 8 (1994) 467.Google Scholar
  43. 43.
    Lam, K.S., Salmon, S.E., Hersch, E.M., Hruby, V.J., Kazmierski, W.M. and Knap, R.J., Nature, 394 (1991) 82.Google Scholar
  44. 44.
    Houghten, R.A., Pinilla, C., Blondelle, S.E., Appel, J.R., Dooley, C.T. and Cuervo, J.H., Nature, 394 (1991) 84.Google Scholar
  45. 45.
    Singh, J., Saldanha, J. and Thornton, J.M., Protein Eng., 4 (1991) 251.Google Scholar
  46. 46.
    Klebe, G., J. Mol. Biol., 237 (1994) 212.Google Scholar
  47. 47.
    Allen, F.H., Bellard, S., Brice, M.D., Cartwright, B.A., Doubleday, A., Higgs, H., Hummelink, T., Hummelink-Peters, B.G., Kennard, O., Motherwell, W.D.W., Rodgers, J.R. and Watson, D.G., Acta Crystallogr., B 35 (1979) 2331.Google Scholar
  48. 48.
    Hurst, T., J. Chem. Inf. Comput. Sci., 34 (1994) 190.Google Scholar
  49. 49.
    Clark, D.E., Jones, G., Willett, P., Kenny, P.W. and Glen, R.C., J. Chem. Inf. Comput. Sci., 34 (1994) 197.Google Scholar
  50. 50.
    Ball, J., Fishleigh, R.V., Greaney, P., Li, J., Marsden, A., Platt, E., Pool, J.L. and Robson, B., In Bawden, D. and Mitchell, E.M. (Eds.) Chemical Structure Information Systems: Beyond the Structure Diagram, Ellis Horwood, Chichester, 1990, pp. 107–123.Google Scholar
  51. 51.
    Robson, B., Ball, J., Fishleigh, R.V., Greaney, P., Li, J., Marsden, A., Platt, E. and Pool, J.L., Biochem. Soc. Symp., 57 (1991) 91.Google Scholar
  52. 52.
    Robson, B. and Platt, E., J. Mol. Biol., 188 (1986) 258.Google Scholar
  53. 53.
    Ramachandran, G.N., Ramakrishnan, C. and Sasiekharan, V., J. Mol. Biol., 7 (1963) 95.Google Scholar
  54. 54.
    Ponder, J.W. and Richards, F.M., J. Mol. Biol., 193 (1987) 775.Google Scholar
  55. 55.
    Ullmann, J.R., Biochem. Biophys. Res. Commun., 23 (1976) 31.Google Scholar
  56. 56.
    Brint, A.T. and Willett, P., J. Mol. Graph., 5 (1987) 49.Google Scholar
  57. 57.
    Kohl, N.E., Emini, E.A., Schlief, W.A., David, L.J., Heimbach, J.C., Dixon, R.A.F., Scolnick, E.M. and Sigal, I.S., Proc. Natl. Acad. Sci. USA, 85 (1988) 4686.Google Scholar
  58. 58.
    McQuade, T.J., Tomaselli, A.G., Liu, L., Karacostas, V., Moss, B., Sawyer, T.K., Heinrikson, R.L. and Tarpley, W.G., Science, 247 (1990) 454.Google Scholar
  59. 59.
    Appelt, K., Perspect. Drug Discov. Design, 1 (1993) 23.Google Scholar
  60. 60.
    Fitzgerald, P.M.D., Curr. Opin. Struct. Biol., 3 (1993) 868.Google Scholar
  61. 61.
    Redshaw, S., Exp. Opin. Invest. Drugs, 3 (1994) 273.Google Scholar
  62. 62.
    Fitzgerald, P.M.D., McKeever, B.M., VanMiddlesworth, J.F., Springer, J.P., Heimbach, J.C., Leu, C.-T., Herber, W.K., Dixon, R.A.F. and Darke, P.L., J. Biol. Chem., 265 (1990) 14209.Google Scholar
  63. 63.
    Waller, C.L., Oprea, T.I., Alessandro, G. and Marshall, G.R., J. Med. Chem., 36 (1994) 4152.Google Scholar
  64. 64.
    Sawyer, T.K., Staples, D.J., Liu, L., Tomasselli, A.G., Hui, J.O., O'Connel, K., Schostarez, H., Hester, J.B., Moon, J., Howe, W.J., Smith, C.W., Decamp, D.L., Craik, C.S., Dunn, B.M., Lowther, W.T., Harris, J., Poorman, R.A., Wlodawer, A., Jaskolski, M. and Heinrikson, R.L., Int. J. Pept. Protein Res., 40 (1992) 274.Google Scholar
  65. 65.
    Fischmann, T.O., Bentley, G.A., Bhat, T.N., Boulot, G., Mariuzza, R.A., Phillips, S.E.V., Tello, D. and Poljak, R.J., J. Biol. Chem., 266 (1991) 12915.Google Scholar
  66. 66.
    Davies, D.R. and Padlan, E.A., Annu. Rev. Biochem., 59 (1990) 439.Google Scholar
  67. 67.
    Gallop, M.A., Barrett, R.W., Dower, W.J., Fodor, S.P.A. and Gordon, E.M., J. Med. Chem., 37 (1994) 1233.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1995

Authors and Affiliations

  • David Frenkel
    • 1
  • David E. Clark
    • 1
  • Jin Li
    • 1
  • Christopher W. Murray
    • 1
  • Barry Robson
    • 1
  • Bohdan Waszkowycz
    • 1
  • David R. Westhead
    • 1
  1. 1.Proteus Molecular Design Ltd.MacclesfieldU.K.

Personalised recommendations