A Discussion of Various Computational Methods for Drug Design

  • Richard A. Lewis
  • Elaine C. Meng
Chapter
Part of the Topics in Molecular and Structural Biology book series (TMSB)

Abstract

Our understanding of the specificity of biological function is based on the principles of molecular recognition.1 The binding and actions of a drug are controlled by the patterns of molecular fields found in the vicinity of the contact surface of the receptor. The goal of drug design is to rationalize observations of the patterns of structure-activity relationships and of ligand-receptor interactions, and to use this knowledge to design novel ligands. Computational methods now play a crucial role in the process of drug design. This review will concentrate on two main topics: the construction of pharmacophoric models (building on structure-activity relationships) and the generation of lead compounds from models of the target receptor site (building on ligand-receptor interactions). There have been significant advances in both areas over the past few years, and it is now timely to examine the progress that has been made, and to look to the future.

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References

  1. 1.
    Dean, P. M. (1987). Molecular Foundations of Drug-Receptor Interaction, Cambridge University Press, CambridgeGoogle Scholar
  2. 2.
    Lewis, R. A. (1991). Meth. Enzymol., 202, 127–156, and references thereinGoogle Scholar
  3. 3.
    Jencks, W. P. (1980). In Chemical Recognition in Biology, ed. Chapeville, F. and Haenni, A.-L., Springer-Verlag, Berlin, p. 3CrossRefGoogle Scholar
  4. 4.
    Sharpe, K., Fine, R. and Honig, B. (1987). Science, 236, 1460–1463CrossRefGoogle Scholar
  5. 5.
    Rullmann, J. A. C. and van Duijnen, P. T. (1990). Reports in Molecular Theory, 1, 1–21Google Scholar
  6. 6.
    Taylor, R. and Kennard, O. (1984). Acc. Chem. Res., 17, 320–326CrossRefGoogle Scholar
  7. 7.
    Legon, A. C. and Milien, D. J. (1992). Chem. Soc. Rev., 21, 71–78CrossRefGoogle Scholar
  8. 8.
    Mitchell, J. B. O. and Price, S. L. (1989). Chem. Phys. Lett., 154, 267–272CrossRefGoogle Scholar
  9. 9.
    Fersht, A. R. (1984). Proc. Roy. Soc. Lond. B, 187, 397–407CrossRefGoogle Scholar
  10. 10.
    Fersht, A. R., Shi, J.-P., Knill-Jones, J., Lowe, D. M., Wilkinson, A. J., Blow, D. M., Brick, P., Carter, P., Waye, M. M. Y. and Winter, G. (1985). Nature, 314, 235–238PubMedCrossRefGoogle Scholar
  11. 11.
    Horovitz, A., Serrano, L., Avron, B., Bycroft, M. and Fersht, A. R. (1990). J. Mol. Biol., 216, 1031–1044PubMedCrossRefGoogle Scholar
  12. 12.
    Doig, A. J. and Williams, D. H. (1992). J. Am. Chem. Soc., 114, 338–343CrossRefGoogle Scholar
  13. 13.
    Chau, P.-L. (1991). PhD Thesis, University of CambridgeGoogle Scholar
  14. 14.
    Grootenhuis, P. D. J. and Kollman, P. A. (1989). J. Am. Chem. Soc., 111, 2152–2158CrossRefGoogle Scholar
  15. 15.
    Fersht, A. R. and Sternberg, M. J. E. (1989). Prot. Eng., 2, 527–530CrossRefGoogle Scholar
  16. 16.
    Harvey, S. C. (1989). Proteins, 5, 78–92PubMedCrossRefGoogle Scholar
  17. 17.
    Warwicker, J. and Watson, H. C. (1982). J. Mol. Biol., 157, 671–679PubMedCrossRefGoogle Scholar
  18. 18.
    Sharp, K. A. and Honig, B. (1990). Ann. Rev. Biophys. Biophys. Chem., 19, 301–332CrossRefGoogle Scholar
  19. 19.
    Gilson, M. K., Sharp, K. A. and Honig, B. (1987). J. Comp. Chem., 9, 327–335CrossRefGoogle Scholar
  20. 20.
    Russell, S. T. and Warshel, A. (1985). J. Mol. Biol., 185, 389–404PubMedCrossRefGoogle Scholar
  21. 21.
    Warshel, A. and Åqvist, J. (1991). Ann. Rev. Biophys. Biophys. Chem., 20, 267–298CrossRefGoogle Scholar
  22. 22.
    Schaefer, M. and Froemmel, C. (1990). J. Mol. Biol., 216, 1045–1066PubMedCrossRefGoogle Scholar
  23. 23.
    Eisenberg, D. and McLachlan, A. D. (1986). Nature, 319, 199–203PubMedCrossRefGoogle Scholar
  24. 24.
    Sharp, K. A., Nicholls, A., Friedman, R. and Honig, B. (1991). Biochemistry, 30, 9686–9697PubMedCrossRefGoogle Scholar
  25. 25.
    Ben-Naim, A. (1980). Hydrophobie Interactions, Plenum Press, New YorkCrossRefGoogle Scholar
  26. 26.
    Dill, K. A. (1985). Biochemistry, 24, 1501–1509PubMedCrossRefGoogle Scholar
  27. 27.
    Chan, H. S. and Dill, K. A. (1990). Proc. Natl Acad. Sci. USA, 87, 6388–6392PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Fersht, A. R. (1985). Enzyme Structure and Mechanism, 2nd edn, Freeman, New YorkGoogle Scholar
  29. 29.
    Hollenberg, M. D. (1990) J. Med. Chem., 5, 1275–1281CrossRefGoogle Scholar
  30. 30.
    Warshel, A., Åqvist, J. and Creighton, S. (1989). Proc. Natl Acad. Sci. USA, 86, 5820–5824PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Sciortino, F., Geiger, A. and Stanley, H. E. (1991). Nature, 354, 218–221CrossRefGoogle Scholar
  32. 32.
    Quiocho, F. A., Wilson, D. K. and Vyas, N. K. (1989). Nature, 340, 404–407PubMedCrossRefGoogle Scholar
  33. 33.
    Blundell, T. L., Sibanda, B. L., Sternberg, M. J. E. and Thornton, J. M. (1987). Nature, 326, 347–352PubMedCrossRefGoogle Scholar
  34. 34.
    Marshall, G. R. (1987). Ann. Rev. Pharmacol. Toxicol., 27, 193–213, and references thereinCrossRefGoogle Scholar
  35. 35.
    Cohen, N. C. (1985). Adv. Drug Res., 14, 42–145Google Scholar
  36. 36.
    Diana, G. D., Treasurywala, A. M., Bailey, T. R., Oglesby, R. C., Pevear, D. C. and Dutko, F. J. (1990). J. Med. Chem., 33, 1306–1311PubMedCrossRefGoogle Scholar
  37. 37.
    Wold, S., Albano, C., Dunn, W. J., Edlund, U., Esbensen, K., Geladi, P., Hellberg, S., Johansson, E., Lindberg, W. and Sjostrom, M. (1984). In Chemometrics, ed. Kowlaski, B. R., Reidel, Dordrecht, pp. 17–96CrossRefGoogle Scholar
  38. 38.
    Liu, R. S. H., Asato, A. E., Denny, M. and Mead, D. (1984). J. Am. Chem. Soc., 106, 8298–8300CrossRefGoogle Scholar
  39. 39.
    Liu, R. S. H. and Mirzadegan, T. (1988). J. Am. Chem. Soc., 110, 8617–8623CrossRefGoogle Scholar
  40. 40.
    Hansch, C. (1969). Acc. Chem. Res., 2, 232–239CrossRefGoogle Scholar
  41. 41.
    Andrea, T. A. and Kalayeh, H. (1991). J. Med. Chem., 34, 2824–2836PubMedCrossRefGoogle Scholar
  42. 42.
    King, R. D., Muggleton, S., Lewis, R. A. and Sternberg, M. J. E. (1993). Proc. Natl Acad. Sci. USA, 89, 11322–11326CrossRefGoogle Scholar
  43. 43.
    Muggleton, S. (1991). New Generation Computing, 8, 295–318CrossRefGoogle Scholar
  44. 44.
    Hansch, C., Ren-Li, L., Blaney, J. M. and Langridge, R. (1982). J. Med. Chem., 25, 777–784PubMedCrossRefGoogle Scholar
  45. 45.
    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. (1985). J. Biol. Chem., 260, 381–391PubMedGoogle Scholar
  46. 46.
    Champness, J. N., Stammers, D. K. and Beddell, C. R. (1986). FEBS Lett., 199, 61–67PubMedCrossRefGoogle Scholar
  47. 47.
    Crippen, G. M. (1987). J. Comp. Chem., 8, 943–955CrossRefGoogle Scholar
  48. 48.
    Sheridan, R. P., Nilakantan, R., Dixon, J. S. and Venkataraghavan, R. (1986). J. Med. Chem., 29, 899–906PubMedCrossRefGoogle Scholar
  49. 49.
    Martin, Y. C. (1992). J. Med. Chem., 35, 2145–2154PubMedCrossRefGoogle Scholar
  50. 50.
    Guner, O. F., Henry, D. R. and Pearlman, R. S. (1992). J. Chem. Inf. Comp. Sci., 32, 101–109CrossRefGoogle Scholar
  51. 51.
    Jakes, S. E. and Willett, P. (1986). J. Mol. Graph., 4, 12–20CrossRefGoogle Scholar
  52. 52.
    Murrall, N. W. and Davies, E. K. (1990). J. Chem. Inf. Comp. Sci., 30, 312–316CrossRefGoogle Scholar
  53. 53.
    Clark, D. E., Willett, P. and Kenny, P. W. (1992). J. Mol. Graph., 10, 194–204PubMedCrossRefGoogle Scholar
  54. 54.
    Crippen, G. M. (1981). Distance Geometry and Conformational Calculations, Research Studies Press, Wiley, ChichesterGoogle Scholar
  55. 55.
    Cramer, R. D. (1988). J. Am. Chem. Soc., 110, 5959–5967PubMedCrossRefGoogle Scholar
  56. 56.
    Marshall, G. R. and Cramer, R. D. (1988). Trends Pharm. Sci., 9, 285–289PubMedCrossRefGoogle Scholar
  57. 57.
    Maggiora, G. and Johnson, M. (1990). Concepts and Applications of Molecular Similarity, Wiley, New YorkGoogle Scholar
  58. 58.
    Dean, P. M., Callow, P. and Chau, P. L. (1988). J. Mol. Graph., 6, 28–34CrossRefGoogle Scholar
  59. 59.
    Barakat, M. T. and Dean, P. M. (1990). J. Comp.-Aided Mol. Design, 4, 295–316CrossRefGoogle Scholar
  60. 60.
    Barakat, M. T. and Dean, P. M. (1990). J. Comp.-Aided Mol. Design, 4, 317–330CrossRefGoogle Scholar
  61. 61.
    Cohen, N. C., Blaney, J. M., Humblet, C., Gund, P. and Barry, D. C. (1990). J. Med. Chem., 33, 883–894PubMedCrossRefGoogle Scholar
  62. 62.
    Goodford, P. J. (1985). J. Med. Chem., 28, 849–857PubMedCrossRefGoogle Scholar
  63. 63.
    Boobbyer, D. N. A., Goodford, P. J., McWhinnie, P. M. and Wade, R. C. (1989). J. Med. Chem., 32, 1083–1094PubMedCrossRefGoogle Scholar
  64. 64.
    Danziger, D. J. and Dean, P. M. (1989). Proc. Roy. Soc. Lond. B, 236, 115–124CrossRefGoogle Scholar
  65. 65.
    Busetta, B., Tickle, I. J. and Blundell, T. L. (1983). J. Appl. Cryst., 16, 432–437CrossRefGoogle Scholar
  66. 66.
    Pattabiraman, N., Levitt, M., Ferrin, T. E. and Langridge, R. (1985). J. Comp. Chem., 6, 432–436CrossRefGoogle Scholar
  67. 67.
    Tomioka, N., Itai, A. and Iitaka, Y. (1987). J. Comp.-Aided Mol. Design, 1, 197–210CrossRefGoogle Scholar
  68. 68.
    Kuntz, I. D., Blaney, J. M., Oatley, S. J., Langridge, R. and Ferrin, T. E. (1982). J. Mol. Biol., 161, 269–288PubMedCrossRefGoogle Scholar
  69. 69.
    DesJarlais, R. L., Sheridan, R. P., Dixon, J. S., Kuntz, I. D. and Venkataraghavan, R. (1986). J. Med. Chem., 29, 2149–2153PubMedCrossRefGoogle Scholar
  70. 70.
    DesJarlais, R. L., Sheridan, R. P., Scibel, G. L., Kuntz, I. D. and Venkataraghavan, R. (1988). J. Med. Chem., 31, 722–729PubMedCrossRefGoogle Scholar
  71. 71.
    Meng, E. C., Shoichet, B. K. and Kuntz, I. D. (1993). J. Comp. Chem., 13, 505–524CrossRefGoogle Scholar
  72. 72.
    Lawrence, M. C. and Davis, P. C. (1992). Proteins, 12, 31–41PubMedCrossRefGoogle Scholar
  73. 73.
    van Gunsteren, W. F. and Berendsen, H. J. C. (1987). J. Comp.-Aided Mol. Design, 1, 171–176CrossRefGoogle Scholar
  74. 74.
    McCammon, J. A. (1987). Science, 238, 486–491PubMedCrossRefGoogle Scholar
  75. 75.
    Brooks, C. L., Karplus, M. and Pettitt, B. M. (1988). Proteins, Wiley, New YorkGoogle Scholar
  76. 76.
    McCammon, J. A. and Harvey, S. C. (1987). Dynamics of Proteins and Nucleic Acids, Cambridge University Press, CambridgeCrossRefGoogle Scholar
  77. 77.
    Deleted in proofGoogle Scholar
  78. 78.
    Jian, F. and Kim, S.-H. (1991). J. Mol. Biol., 219, 79–102CrossRefGoogle Scholar
  79. 79.
    Shoichet, B. K. and Kuntz, I. D. (1991). J. Mol. Biol., 221, 327–346PubMedCrossRefGoogle Scholar
  80. 80.
    Shoichet, B. K., Bodian, D. L. and Kuntz, I. D. (1992). J. Comp. Chem., 13, 380–397CrossRefGoogle Scholar
  81. 81.
    Goodsell, D. S. and Olson, A. J. (1990). Proteins, 8, 195–202PubMedCrossRefGoogle Scholar
  82. 82.
    Weiner, S. J., Kollman, P. A., Case, D. A., Singh, U. C., Ghio, C., Alagona, G., Profeta, S. and Weiner, P. (1984). J. Am. Chem. Soc., 106, 765–784CrossRefGoogle Scholar
  83. 83.
    Smellie, A. S., Crippen, G. M. and Richards, W. G. (1991). J. Chem. Inf. Comp. Sci., 31, 386CrossRefGoogle Scholar
  84. 84.
    Leach, A. R. and Kuntz, I. D. (1992). J. Comp. Chem., 13, 730–748CrossRefGoogle Scholar
  85. 85.
    Leach, A. R. and Prout, K. (1990). J. Comp. Chem., 11, 1193CrossRefGoogle Scholar
  86. 86.
    Lewis, R. A. and Dean, P. M. (1989). Proc. Roy. Soc. Lond. B, 236, 125–140CrossRefGoogle Scholar
  87. 87.
    Lewis, R. A. and Dean, P. M. (1989). Proc. Roy. Soc. Lond. B, 236, 141–162CrossRefGoogle Scholar
  88. 88.
    Adamson, G. W., Creasey, S. E., Eakins, J. P. and Lynch, M. F. (1973). J. Chem. Soc. Perkin Trans. I, 1973, 2071–2076Google Scholar
  89. 89.
    Lewis, R. A. (1990). J. Comp.-Aided Mol. Design, 4, 205–210CrossRefGoogle Scholar
  90. 90.
    Lewis, R. A. (1989). Sixth European Seminar on Computer-Aided Molecular Design, LondonGoogle Scholar
  91. 91.
    Lewis, R. A. (1990). In Proceedings of Scientific Computing and Automation, ed. Karjalainen, E. J., Elsevier, AmsterdamGoogle Scholar
  92. 92.
    Lewis, R. A., Roe, D. C., Huang, C., Ferrin, T. E., Langridge, R. and Kuntz, I. D. (1992). J. Mol. Graph., 10, 66–78PubMedCrossRefGoogle Scholar
  93. 93.
    Moon, J. B. and Howe, W. J. (1991). Proteins, 11, 314–328PubMedCrossRefGoogle Scholar
  94. 94.
    Nishibata, Y. and Itai, A. (1991). Tetrahedron, 47, 8985–8990CrossRefGoogle Scholar
  95. 95.
    Nilakantan, R., Bauman, N. and Venkataraghavan, R. (1991). J. Chem. Inf. Comp. Sci., 31, 527–530CrossRefGoogle Scholar
  96. 96.
    Bohm, H.-J. (1992). J. Comp.-Aided Mol. Design, 6, 61–78CrossRefGoogle Scholar
  97. 97.
    Lewis, R. A. (1992). J. Mol. Graph., 10, 131–143PubMedCrossRefGoogle Scholar
  98. 98.
    Go, N. and Scheraga H. A. (1970). Macromolecules, 3, 178–187CrossRefGoogle Scholar
  99. 99.
    Bruccoleri, R. E. and Karplus, M. (1985). Macromolecules, 18, 2767–2773CrossRefGoogle Scholar
  100. 100.
    Bruccoleri, R. E. and Karplus, M. (1987). Biopolymers, 26, 137–168PubMedCrossRefGoogle Scholar
  101. 101.
    Bruccoleri, R. E., Haber, E. and Novotny, J. (1988). Nature, 335, 564–568PubMedCrossRefGoogle Scholar
  102. 102.
    Hassall, C. H., Krohn, A., Moody, C. J. and Thomas, W. A. (1984). J. Chem. Soc. Perkin Trans. I, 155–164Google Scholar
  103. 103.
    Huff, J. R. (1991). J. Med. Chem., 34, 2305–2314PubMedCrossRefGoogle Scholar
  104. 104.
    Miller, M., Schneider, J., Sathyanarayana, B. K., Toth, M. V., Marshall, G. R., Clawson, L., Selk, L., Kent, S. B. H. and Wlodawer, A. (1989). Science, 246, 1149–1152PubMedCrossRefGoogle Scholar
  105. 105.
    Erickson, J., Neidhart, D. J., VanDrie, J., Kempf, D. J., Wang, X. C., Norbeck, D. W., Plattner, J. J., Rittenhouse, J. W., Turon, M., Wideburg, N., Kohlbrenner, W. E., Simmer, R., Helfrich, R., Paul, D. A. and Knigge, M. (1990). Science, 249, 527–533PubMedCrossRefGoogle Scholar
  106. 106.
    Thompson, W. S., 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. (1992). J. Med. Chem., 35, 1685–1701PubMedCrossRefGoogle Scholar
  107. 107.
    DesJarlais, R. L., Scibel, G. L., Kuntz, I. D., Furth, P. S., Alvarez, J. C., Ortiz de Montellano, P. R., DeCamp, D. L., Babe, L. M. and Craik, C. S. (1990). Proc. Natl Acad. Sci. USA, 87, 6644–6648PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Brinkworth, R. L, Woon, T. C. and Fairlie, D. P. (1991). Biochem. Biophys. Res. Commun., 176, 241–246PubMedCrossRefGoogle Scholar
  109. 109.
    Matthews, D. A., Appelt, K., Oatley, S. J. and Xuong, N. H. (1990). J. Mol. Biol., 214, 923–936PubMedCrossRefGoogle Scholar
  110. 110.
    Appelt, K., Bacquet, R. J., Bartlett, C. A., Booth, C. L. J., Freer, S. T., Fuhry, M. A. M., Gehring, M. R., Herrmann, S. M., Howland, E. F., Janson, C. A., Jones, T. A., Kan, C.-C., Kathadekar, 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., Villafrance, J. E., Ward, R. W., Webber, S., Webber, S. E., Welsh, K. M. and White, J. (1991). J. Med. Chem., 34, 1925–1934PubMedCrossRefGoogle Scholar
  111. 111.
    Matthews, D. A., Villafranca, T. E., Janson, C. A., Smith, W. W., Welsh, K. and Freer, S. (1990). J. Mol. Biol., 214, 937–948PubMedCrossRefGoogle Scholar

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© J. G. Vinter and M. Gardner 1994

Authors and Affiliations

  • Richard A. Lewis
  • Elaine C. Meng

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