Journal of Computer-Aided Molecular Design

, Volume 9, Issue 1, pp 13–32 | Cite as

PRO_LIGAND: An approach to de novo molecular design. 1. Application to the design of organic molecules

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

Summary

An approach to de novo molecular design, PRO_LIGAND, has been developed that, in the environment of a large, integrated molecular design and simulation system, provides a unified framework for the generation of novel molecules which are either similar or complementary to a specified target. The approach is based on a methodology that has proved to be effective in other studies-placing molecular fragments upon target interaction sites-but incorporates many novel features such as the use of a rapid graph-theoretical algorithm for fragment placing, a generalised driver for structure generation which offers a large variety of fragment assembly strategies to the user and the pre-screening of library fragments. After a detailed description of the relevant modules of the package, PRO_LIGAND's efficacy in aiding rational drug design is demonstrated by its ability to design mimics of methotrexate and potential inhibitors for dihydrofolate reductase and HIV-1 protease.

Keywords

Drug design De novo design Enzyme inhibitors Graph theory 

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.
    Fesik, S.W., J. Biomol. NMR, 3 (1993) 261.Google Scholar
  3. 3.
    Navia, M.A. and Murcko, M.A., Curr. Opin. Struct. Biol., 2 (1992) 202.Google Scholar
  4. 4.
    Kuntz, I.D., Science, 257 (1992) 1078.Google Scholar
  5. 5.
    Bugg, C.E., Carson, W.M. and Montgomery, J.A., Sci. Am., 269 (1993) 60.Google Scholar
  6. 6.
    Ealick, S.E. and Armstrong, S.R., Curr. Opin. Struct. Biol., 3 (1993) 861.Google Scholar
  7. 7.
    Reich, S.H. and Webber, S.E., Perspect. Drug Discov. Design, 1 (1993) 371.Google Scholar
  8. 8.
    Greer, J., Erickson, J.W., Baldwin, J.J. and Varney, M.D., J. Med. Chem., 37 (1994) 1035.Google Scholar
  9. 9.
    Verlinde, C.L.M.J. and Hol, W.G.J., Structure, 2 (1994) 577.Google Scholar
  10. 10.
    Blundell, T.L., Sibanda, B.L., Sternberg, M.J.E. and Thornton, J.M., Nature, 326 (1987) 347.Google Scholar
  11. 11.
    Mayer, D., Naylor, C.B., Motoc, I. and Marshall, G.R., J. Comput.-Aided Mol. Design, 1 (1987) 3.Google Scholar
  12. 12.
    Sheridan, R.P., Nilakantan, R., Dixon, J.S. and Venkataraghavan, R., J. Med. Chem., 29 (1986) 899.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.
    Cramer, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 10 (1988) 5959.Google Scholar
  15. 15.
    Moon, J.B. and Howe, W.J., Protein Struct. Funct. Genet., 11 (1991) 314.Google Scholar
  16. 16.
    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
  17. 17.
    Miranker, A. and Karplus, M., Protein Struct. Funct. Genet., 11 (1991) 29.Google Scholar
  18. 18.
    Caflisch, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.Google Scholar
  19. 19.
    Nishibata, Y. and Itai, A., Tetrahedron, 47 (1991) 8985.Google Scholar
  20. 20.
    Nishibata, Y. and Itai, A., J. Med. Chem., 36 (1993) 2921.Google Scholar
  21. 21.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.Google Scholar
  22. 22.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 593.Google Scholar
  23. 23.
    Böhm, H.-J., In Kubinyi, H. (Ed.) 3D QSAE in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, 1993, pp. 386–405.Google Scholar
  24. 24.
    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
  25. 25.
    Rotstein, S.H. and Murcko, M.A., J. Comput.-Aided Mol. Design, 7 (1993) 23.Google Scholar
  26. 26.
    Rotstein, S.H. and Murcko, M.A., J. Med. Chem., 36 (1993) 1700.Google Scholar
  27. 27.
    Gillet, V.J., Johnson, A.P., Mata, P., Sike, S. and Williams, P., J. Comput.-Aided Mol. Design, 7 (1993) 127.Google Scholar
  28. 28.
    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
  29. 29.
    Pearlman, D.A. and Murcko, M.A., J. Comput. Chem., 14 (1993) 1184.Google Scholar
  30. 30.
    Tschinke, V. and Cohen, N.C., J. Med. Chem., 36 (1993) 3863.Google Scholar
  31. 31.
    Ho, C.W.M. and Marshall, G.R., J. Comput.-Aided Mol. Design, 7 (1993) 623.Google Scholar
  32. 32.
    Leach, A.R. and Lewis, R.A., J. Comput. Chem., 15 (1994) 233.Google Scholar
  33. 33.
    Leach, A.R. and Kilvington, S.R., J. Comput.-Aided Mol. Design, 8 (1994) 283.Google Scholar
  34. 34.
    Eisen, M.B., Wiley, D.C., Karplus, M. and Hubbard, R.E., Protein Struct. Funct. Genet., 19 (1994) 199.Google Scholar
  35. 35.
    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
  36. 36.
    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
  37. 37.
    Frenkel, D., Clark, D.E., Li, J., Murray, C.W., Robson, B., Waszkowycz, B. and Westhead, D.R., J. Comput.-Aided Mol. Design, submitted for publication.Google Scholar
  38. 38.
    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
  39. 39.
    Klebe, G., J. Mol. Biol., 237 (1994) 212.Google Scholar
  40. 40.
    Goldberg, D.E., Genetic Algorithms in Search, Optimization and Machine Learning, Addison-Wesley, Reading, MA, 1989.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) in press.Google Scholar
  42. 42.
    Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.Google Scholar
  43. 43.
    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
  44. 44.
    Weiner, S.J., Kollman, P.A., Nguyen, D.T. and Case, D.A., J. Comput. Chem., 7 (1986) 230.Google Scholar
  45. 45.
    Robson, B. and Platt, E., J. Mol. Biol., 188 (1986) 258.Google Scholar
  46. 46.
    Morley, S.D., Abraham, R.J., Haworth, I.S., Jackson, D.E., Saunders, M.R. and Vinter, J.G., J. Comput.-Aided Mol. Design, 5 (1991) 475.Google Scholar
  47. 47.
    Bartlett, P.A., Shea, G.T., Telfer, S.J. and Waterman, S., In Roberts, S.M., Ley, S.V. and Campbell, M.M. (Eds.) Chemical and Biological Problems in Molecular Recognition, ROyal Society of Chemistry, Cambridge, 1989, pp. 182–196.Google Scholar
  48. 48.
    Lauri, G. and Bartlett, P.A., J. Comput.-Aided Mol. Design, 8 (1994) 51.Google Scholar
  49. 49.
    Ullmann, J.R., J. Assoc. Comput. Machinery, 23 (1976) 31.Google Scholar
  50. 50.
    Brint, A.T. and Willett, P., J. Mol. Graph., 5 (1987) 49.Google Scholar
  51. 51.
    Golender, V.E. and Vorpagel, E.R., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, 1993, pp. 137–149.Google Scholar
  52. 52.
    Bron, C. and Kerbosch, J., Commun. Assoc. Comput. Machinery, 16 (1973) 575.Google Scholar
  53. 53.
    Brint, A.T. and Willett, P., J. Chem. Inf. Comput. Sci., 27 (1987) 152.Google Scholar
  54. 54.
    Ho, C.W.M. and Marshall, G.R., J. Comput.-Aided Mol. Design, 7 (1993) 3.Google Scholar
  55. 55.
    Kuhl, F.S., Crippen, G.M. and Friesen, D.K., J. Comput. Chem., 5 (1984) 24.Google Scholar
  56. 56.
    Smellie, A.S., Crippen, G.M. and Richards, W.G., J. Chem. Inf. Comput. Sci., 31 (1991) 386.Google Scholar
  57. 57.
    Grindley, H.M., Artymiuk, P.J., Rice, D.W. and Willett, P., J. Mol. Biol., 229 (1993) 707.Google Scholar
  58. 58.
    Jakes, S.E. and Willett, P., J. Mol. Graph., 4 (1986) 12.Google Scholar
  59. 59.
    Willett, P., Similarity and Clustering in Chemical Information Systems, Research Studies Press, Letchworth, 1987.Google Scholar
  60. 60.
    Bawden, D., In Warr, W.A. (Ed.) Chemical Structures 2: The International Language of Chemistry, Springer, Heidelberg, 1993, pp. 383–388.Google Scholar
  61. 61.
    Martin, Y.C., Bures, M.G. and Willett, P., In Lipkowitz, K.B. and Boyd, D.B. (Eds.) Reviews in Computational Chemistry, Vol. 1, VCH, New York, NY, 1990, pp. 213–263.Google Scholar
  62. 62.
    Moock, T.E., Henry, D.R., Ozkabak, A.G. and Alamgir, M., J. Chem. Inf. Comput. Sci., 34 (1994) 184.Google Scholar
  63. 63.
    Clark, D.E., Jones, G., Willett, P., Kenny, P.A. and Glen, R.C., J. Chem. Inf. Comput. Sci., 34 (1994) 197.Google Scholar
  64. 64.
    Kuyper, L.F., In Perun, T.J. and Propst, C.L. (Eds.) Computer-Aided Drug Design, Marcel Dekker, New York, NY, 1989, pp. 327–369.Google Scholar
  65. 65.
    Ramnarayan, K., Hausheer, F.H. and Singh, U.C., CDA News, 8 (1993) 18.Google Scholar
  66. 66.
    Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.Google Scholar
  67. 67.
    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
  68. 68.
    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
  69. 69.
    Appelt, K., Perspect. Drug Discov. Design, 1 (1993) 23.Google Scholar
  70. 70.
    Fitzgerald, P.M.D., Curr. Opin. Struct. Biol., 3 (1993) 868.Google Scholar
  71. 71.
    Redshaw, S., Exp. Opin. Invest. Drugs, 3 (1994) 273.Google Scholar
  72. 72.
    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

Copyright information

© ESCOM Science Publishers B.V 1995

Authors and Affiliations

  • David E. Clark
    • 1
  • David Frenkel
    • 1
  • Stephen A. Levy
    • 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