Journal of Computer-Aided Molecular Design

, Volume 9, Issue 2, pp 139–148 | Cite as

PRO_LIGAND: An approach to de novo molecular design. 3. A genetic algorithm for structure refinement

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

Summary

Recently, the development of computer programs which permit the de novo design of molecular structures satisfying a set of steric and chemical constraints has become a burgeoning area of research and many operational systems have been reported in the literature. Experience with PRO_LIGAND—the de novo design methodology embodied in our in-house molecular design and simulation system PRO-METHEUS—has suggested that the addition of a genetic algorithm (GA) structure refinement procedure can ‘add value’ to an already useful tool. Starting with the set of designed molecules as an initial population, the GA can combine features from both high- and low-scoring structures and, over a number of generations, produce individuals of better score than any of the starting structures. This paper describes how we have implemented such a procedure and demonstrates its efficacy in improving two sets of molecules generated by different de novo design projects.

Keywords

Drug design De novo design Genetic algorithms 

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References

  1. 1.
    Martin, Y.C., Methods Enzymol., 203 (1991) 587.Google Scholar
  2. 2.
    Dixon, J.S., Trends Biotechnol., 10 (1992) 357.Google Scholar
  3. 3.
    Moon, J.B. and Howe, W.J., Protein Struct. Funct. Genet., 11 (1991) 314.Google Scholar
  4. 4.
    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
  5. 5.
    Miranker, A. and Karplus, M., Protein Struct. Funct. Genet., 11 (1991) 29.Google Scholar
  6. 6.
    Caflisch, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.Google Scholar
  7. 7.
    Nishibata, Y. and Itai, A., Tetrahedron, 47 (1991) 8985.Google Scholar
  8. 8.
    Nishibata, Y. and Itai, A., J. Med. Chem., 36 (1993) 2921.Google Scholar
  9. 9.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.Google Scholar
  10. 10.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 593.Google Scholar
  11. 11.
    Böhm, H.-J., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, 1993, pp. 386–405.Google Scholar
  12. 12.
    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
  13. 13.
    Rotstein, S.H. and Murcko, M.A., J. Comput.-Aided Mol. Design, 7 (1993) 23.Google Scholar
  14. 14.
    Rotstein, S.H. and Murcko, M.A., J. Med. Chem., 36 (1993) 1700.Google Scholar
  15. 15.
    Gillet, V.J., Johnson, A.P., Mata, P., Sike, S. and Williams, P., J. Comput.-Aided Mol. Design, 7 (1993) 127.Google Scholar
  16. 16.
    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
  17. 17.
    Pearlman, D.A. and Murcko, M.A., J. Comput. Chem., 14 (1993) 1184.Google Scholar
  18. 18.
    Tschinke, V. and Cohen, N.C., J. Med. Chem., 36 (1993) 3863.Google Scholar
  19. 19.
    Ho, C.W.M. and Marshall, G.R., J. Comput.-Aided Mol. Design, 7 (1993) 623.Google Scholar
  20. 20.
    Leach, A.R. and Lewis, R.A., J. Comput. Chem., 15 (1994) 233.Google Scholar
  21. 21.
    Leach, A.R. and Kilvington, S.R., J. Comput.-Aided Mol. Design, 8 (1994) 283.Google Scholar
  22. 22.
    Eisen, M.B., Wiley, D.C., Karplus, M. and Hubbard, R.E., Protein Struct. Funct. Genet., 19 (1994) 199.Google Scholar
  23. 23.
    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
  24. 24.
    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
  25. 25.
    Klebe, G., J. Mol. Biol., 237 (1994) 212.Google Scholar
  26. 26.
    Holland, J.H., Adaptation in Natural and Artificial Systems, University of Michigan Press, Ann Arbor, MI, 1975.Google Scholar
  27. 27.
    Holland, J.H., Sci. Am., 267 (1992) 44.Google Scholar
  28. 28.
    Goldberg, D.E., Genetic Algorithms in Search, Optimization and Machine Learning, Addison-Wesley, Reading, MA, 1989.Google Scholar
  29. 29.
    Davis, L. (Ed.) Handbook of Genetic Algorithms, Van Nostrand Reinhold, New York, NY, 1991.Google Scholar
  30. 30.
    Lucasius, C.B. and Kateman, G., Chemometrics Intelligent Lab. Syst., 19 (1993) 1.Google Scholar
  31. 31.
    South, M.C., Wetherill, G.B. and Tham, M.T., J. Appl. Stats., 20 (1993) 153.Google Scholar
  32. 32.
    Judson, R.S., J. Phys. Chem., 96 (1992) 10102.Google Scholar
  33. 33.
    Dandekar, T. and Argos, P., Protein Eng., 5 (1992) 637.Google Scholar
  34. 34.
    Dandekar, T. and Argos, P., J. Mol. Biol., 236 (1994) 844.Google Scholar
  35. 35.
    Sun, S., Protein Sci., 2 (1993) 762.Google Scholar
  36. 36.
    Unger, R. and Moult, J., J. Mol. Biol., 231 (1993) 75.Google Scholar
  37. 37.
    Jones, D.T., Protein Sci., 3 (1994) 567.Google Scholar
  38. 38.
    Judson, R.S., Jaeger, E.P. and Treasurywala, A.M., J. Mol. Struct. (THEOCHEM), 308 (1994) 191.Google Scholar
  39. 39.
    McGarrah, D.B. and Judson, R.S., J. Comput. Chem., 14 (1993) 1385.Google Scholar
  40. 40.
    Judson, R.S., Jaeger, E.P., Treasurywala, A.M. and Peterson, M.L., J. Comput. Chem., 14 (1993) 1407.Google Scholar
  41. 41.
    Clark, D.E., Jones, G., Willett, P., Kenny, P.W. and Glen, R.C., J. Chem. Inf. Comput. Sci., 34 (1994) 197.Google Scholar
  42. 42.
    Blommers, M.J.J., Lucasius, C.B., Kateman, G. and Kaptein, R., Biopolymers, 32 (1992) 45.Google Scholar
  43. 43.
    Judson, R.S., Colvin, M.E., Meza, J.C., Huffer, A. and Gutierrez, D., Int. J. Quantum Chem., 44 (1992) 277.Google Scholar
  44. 44.
    Tufféry, P., Etchebest, C., Hazout, S. and Lavery, R., J. Comput. Chem., 14 (1993) 790.Google Scholar
  45. 45.
    Sanderson, P.N., Glen, R.C., Payne, A.W.R., Hudson, B.D., Heide, C., Tranter, G.E., Doyle, P.D. and Harris, C.J., Int. J. Pept. Protein Res., 43 (1994) 588.Google Scholar
  46. 46.
    Le Grand, S.M. and MerzJr., K.M., J. Global Opt., 3 (1993) 49.Google Scholar
  47. 47.
    Brodmeier, T. and Pretsch, E., J. Comput. Chem., 15 (1994) 588.Google Scholar
  48. 48.
    May, A.C.W. and Johnson, M.S., Protein Eng., 7 (1994) 475.Google Scholar
  49. 49.
    Payne, A.W.R. and Glen, R.C., J. Mol. Graph., 11 (1993) 74.Google Scholar
  50. 50.
    Rogers, D. and Hopfinger, A.J., J. Chem. Inf. Comput. Sci., 34 (1994) 854.Google Scholar
  51. 51.
    Leardi, R., J. Chemometrics, 8 (1994) 65.Google Scholar
  52. 52.
    Walters, D.E. and Hinds, R.M., J. Med. Chem., 37 (1994) 2527.Google Scholar
  53. 53.
    Blaney, J.M., Dixon, J.S. and Weininger, D., Paper presented at the Molecular Graphics Society Meeting on Binding Sites, York, U.K., March 1993.Google Scholar
  54. 54.
    Glen, R.C., Paper presented at the Molecular Graphics Society Meeting on Binding Sites, York, U.K., March 1993.Google Scholar
  55. 55.
    Cramer, R.D., CDA News, 8 (1993) 32.Google Scholar
  56. 56.
    Radcliffe, N.J., In Männer, R. and Manderick, B. (Eds.) Parallel Problem Solving from Nature, Vol. 2, Elsevier, Amsterdam, 1992, pp. 259–268.Google Scholar
  57. 57.
    Herndon, W.C., In King, R.B. (Ed.) Chemical Applications of Topology and Graph Theory, Elsevier, Amsterdam, 1983, pp. 231–242.Google Scholar
  58. 58.
    Morgan, H.L., J. Chem. Doc., 5 (1965) 107.Google Scholar
  59. 59.
    Moreau, G., Nouv. J. Chim., 4 (1980) 17.Google Scholar
  60. 60.
    Kuyper, L.F., In Perum, T.J. and Propst, C.L. (Eds.) Computer-Aided Drug Design, Marcel Dekker, New York, NY, 1989, pp. 327–369.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1995

Authors and Affiliations

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

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