Journal of Computer-Aided Molecular Design

, Volume 11, Issue 3, pp 209–228 | Cite as

A comparison of heuristic search algorithms for molecular docking

  • David R. Westhead
  • David E. Clark
  • Christopher W. Murray


This paper describes the implementation and comparison of four heuristic search algorithms (genetic algorithm, evolutionary programming, simulated annealing and tabu search) and a random search procedure for flexible molecular docking. To our knowledge, this is the first application of the tabu search algorithm in this area. The algorithms are compared using a recently described fast molecular recognition potential function and a diverse set of five protein–ligand systems. Statistical analysis of the results indicates that overall the genetic algorithm performs best in terms of the median energy of the solutions located. However, tabu search shows a better performance in terms of locating solutions close to the crystallographic ligand conformation. These results suggest that a hybrid search algorithm may give superior results to any of the algorithms alone.

Ligand–protein docking Molecular recognition Evolutionary algorithms Simulated annealing Tabu search 


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  1. 1.
    Blaney, J.M. and Dixon, J.S., Perspect. Drug Discov. Design, 1 (1993) 301.Google Scholar
  2. 2.
    Jones, G. and Willett, P., Curr. Opin. Biotechnol., 6 (1995) 652.Google Scholar
  3. 3.
    Lybrand, T.P., Curr. Opin. Struct. Biol., 5 (1995) 224.Google Scholar
  4. 4.
    Rosenfeld, R., Vajda, S. and Delisi, C., Annu. Rev. Biophys., Biomol. Struct., 24 (1995) 677.Google Scholar
  5. 5.
    Gschwend, D.A., Good, A.C. and Kuntz, I.D., J. Mol. Recog., 9 (1996) 175.Google Scholar
  6. 6.
    Lengauer, T. and Rarey, M., Curr. Opin. Struct. Biol., 6 (1996) 402.Google Scholar
  7. 7.
    Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.Google Scholar
  8. 8.
    Goodsell, D.S. and Olson, A.J., Proteins Struct. Funct. Genet., 8 (1990) 195.Google Scholar
  9. 9.
    Yamada, M. and Itai, A., Chem. Pharm. Bull., 41 (1993) 1200.Google Scholar
  10. 10.
    Yamada, M. and Itai, A., Chem. Pharm. Bull., 41 (1993) 1203.Google Scholar
  11. 11.
    Leach, A.R., J. Mol. Biol., 235 (1994) 345.Google Scholar
  12. 12.
    Miller, M.D., Kearsley, S.K., Underwood, D.J. and Sheridan, R.P., J. Comput.-Aided Mol. Design, 8 (1994) 153.Google Scholar
  13. 13.
    Clark, K.P. and Ajay, J. Comput. Chem., 16 (1995) 1210.Google Scholar
  14. 14.
    Gehlhaar, D.K., Verkhivker, G.M., Rejto, P.A., Sherman, C.J., Fogel, D.B., Fogel, L.J. and Freer, S.T., Chem. Biol., 2 (1995) 317.Google Scholar
  15. 15.
    Gehlhaar, D.K., Verkhivker, G.M., Rejto, P.A., Fogel, D.B., Fogel, L.J. and Freer, S.T., In McDonnell, J.R., Reynolds, R.G. and Fogel, D.B. (Eds.) Evolutionary Programming IV (Proceedings of the Fourth Annual Conference on Evolutionary Programming), MIT Press, Cambridge, MA, U.S.A., 1995, pp. 615–627.Google Scholar
  16. 16.
    Jones, G., Willett, P. and Glen, R.C., J. Mol. Biol., 245 (1995) 43.Google Scholar
  17. 17.
    Judson, R.S., Tan, Y.T., Mori, E., Melius, C., Jaeger, E.P., Treasurywala, A.M. and Mathiowetz, A., J. Comput. Chem., 16 (1995) 1405.Google Scholar
  18. 18.
    Oshiro, C.M., Kuntz, I.D. and Dixon, J.S., J. Comput.-Aided Mol. Design, 9 (1995) 113.Google Scholar
  19. 19.
    Goodsell, D.S., Morris, G.M. and Olson, A.J., J. Mol. Recog., 9 (1996) 1.Google Scholar
  20. 20.
    Morris, G.M., Goodsell, D.S., Huey, R. and Olson, A.J., J. Comput.-Aided Mol. Design, 10 (1996) 293.Google Scholar
  21. 21.
    Rarey, M., Wefing, S. and Lengauer, T., J. Comput.-Aided Mol. Design, 10 (1996) 41.Google Scholar
  22. 22.
    Rarey, M., Kramer, B., Lengauer, T. and Klebe, G., J. Mol. Biol., 261 (1996) 470.Google Scholar
  23. 23.
    Welch, W., Ruppert, J. and Jain, A.N., Chem. Biol., 3 (1996) 449.Google Scholar
  24. 24.
    Abagyan, R.A., Totrov, M. and Kuznetsov, D., J. Comput. Chem., 15 (1994) 488.Google Scholar
  25. 25.
    Read, R.J., Hart, T.N., Cummings, M.D. and Ness, S.R., Supramol. Chem., 6 (1995) 135.Google Scholar
  26. 26.
    Verkhivker, G.M., Rejto, P.A., Gehlhaar, D.K. and Freer, S.T., Proteins Struct. Funct. Genet., 250 (1996) 342.Google Scholar
  27. 27.
    Kirkpatrick, S., Gelatt, C.D. and Vecchi, M.P., Science, 220 (1983) 671.Google Scholar
  28. 28.
    Metropolis, N., Rosenbluth, A.W., Rosenbluth, M.N., Teller, A.H. and Teller, E., J. Chem. Phys., 21 (1953) 1087.Google Scholar
  29. 29.
    Szu, H.H. and Hartley, R.L., Phys. Lett., A122 (1987) 157.Google Scholar
  30. 30.
    Fogel, D., Evolutionary Computation: Towards a New Philosophy of Machine Intelligence, IEEE Press, Piscataway, NJ, U.S.A., 1995, pp. 121–186.Google Scholar
  31. 31.
    Yao, X. and Liu, Y., In Fogel, L.J., Angeline, P.J. and Bäck, T. (Eds.) Evolutionary Programming V (Proceedings of the Fifth Annual Conference on Evolutionary Programming), MIT Press, Cambridge, MA, U.S.A., 1996, pp. 257–266.Google Scholar
  32. 32.
    Saravanan, N., Fogel, D.B. and Nelson, K.M., BioSystems, 36 (1995) 157.Google Scholar
  33. 33.
    Glover, F. and Laguna, M., In Reeves, C.R. (Ed.) Modern Heuristic Techniques for Combinatorial Problems, Blackwell, Oxford, U.K., 1993, pp. 70–150.Google Scholar
  34. 34.
    Cvijovic, D. and Klinowski, J., Science, 267 (1995) 664.Google Scholar
  35. 35.
    Kvasnička, V. and Pospíchal, J., J. Chem. Inf. Comput. Sci., 34 (1994) 1109.Google Scholar
  36. 36.
    Goodman, J.M. and Still, W.C., J. Comput. Chem., 12 (1991) 1110.Google Scholar
  37. 37.
    Huber, T., Torda, A. and Van Gunsteren, W.F., J. Comput.-Aided Mol. Design, 8 (1994) 695.Google Scholar
  38. 38.
    Smellie, A., Teig, S.L. and Towbin, P., J. Comput. Chem., 16 (1995) 171.Google Scholar
  39. 39.
    Goldberg, D.E., Genetic Algorithms in Search, Optimization, and Machine Learning, Addison-Wesley, Reading, MA, U.S.A., 1989.Google Scholar
  40. 40.
    Press, W.H., Teukolsky, S.A., Vetterling, W.T. and Flannery, B.P., Numerical Recipes in C: The Art of Scientific Computing, 2nd ed., Cambridge University Press, Cambridge, U.K., 1992, pp. 412–420.Google Scholar
  41. 41.
    Gardner, M.J. and Altman, D.G., Statistics with Confidence, British Medical Journal, Tavistock Square, London, U.K., 1989, pp. 74–76.Google Scholar
  42. 42.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.Google Scholar
  43. 43.
    InsightII/Discover, v. 95.0, Molecular Simulations Inc., San Diego, CA, U.S.A., 1996.Google Scholar
  44. 44.
    Poornima, C.S. and Dean, P.M., J. Comput.-Aided Mol. Design, 9 (1995) 500.Google Scholar
  45. 45.
    Poornima, C.S. and Dean, P.M., J. Comput.-Aided Mol. Design, 9 (1995) 513.Google Scholar
  46. 46.
    Poornima, C.S. and Dean, P.M., J. Comput.-Aided Mol. Design, 9 (1995) 521.Google Scholar
  47. 47.
    Guida, W.C., Bohacek, R.S. and Erion, M.D., J. Comput. Chem., 13 (1992) 214.Google Scholar
  48. 48.
    Mayo, S.L., Olafson, B.D. and Goddard, W.A., J. Phys. Chem., 94 (1990) 8897.Google Scholar
  49. 49.
    Gehlhaar, D.K., private communication, 1996.Google Scholar
  50. 50.
    Gschwend, D.A. and Kuntz, I.D., J. Comput.-Aided Mol. Design, 10 (1996) 123.Google Scholar
  51. 51.
    Meza, J.C., Judson, R.S., Faulkner, T.R. and Treasurywala, A.M., J. Comput. Chem., 17 (1996) 1142.Google Scholar
  52. 52.
    Montoya, F. and Dubois, J.M., Europhys. Lett., 22 (1993) 79.Google Scholar
  53. 53.
    Kido, T., Takagi, K. and Nakanishi, M., Informatica, 18 (1994) 399.Google Scholar
  54. 54.
    Mahfoud, S.W. and Goldberg, D.E., Paral. Comput., 21 (1995) 1.Google Scholar
  55. 55.
    Tang, R.Y., Yang, S.Y., Li, Y., Wen, G. and Mei, T.M., IEEE Trans. Magnetics, 32 (1996) 1326.Google Scholar
  56. 56.
    Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Mol. Biol., 257 (1982) 13650.Google Scholar
  57. 57.
    Burmeister, W.P., Henrissat, B., Bosso, C., Cusack, S. and Ruigrok, R.W.H., Structure, 1 (1993) 19.Google Scholar
  58. 58.
    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
  59. 59.
    Brandstetter, H., Turk, D., Hoeffken, H.W., Grosse, D., Stuerzebecher, J., Martin, P.D., Edwards, B.F.P. and Bode, W., J. Mol. Biol., 226 (1992) 1085.Google Scholar

Copyright information

© Kluwer Academic Publishers 1997

Authors and Affiliations

  • David R. Westhead
    • 1
  • David E. Clark
    • 1
  • Christopher W. Murray
    • 1
  1. 1.Proteus Molecular Design Ltd., Proteus HouseCheshireU.K.

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