Journal of Computer-Aided Molecular Design

, Volume 7, Issue 1, pp 23–43

GenStar: A method for de novo drug design

  • Sergio H. Rotstein
  • Mark A. Murcko
Research Papers


A novel method, which we call GenStar, has been developed to suggest chemically reasonable structures which fill the active sites of enzymes. The proposed molecules provide good steric contact with the enzyme and exist in low-energy conformations. These structures are composed entirely of sp3 carbons which are grown sequentially, but which can also branch or form rings. User-selected enzyme seed atoms may be used to determine the area in which structure generation begins. Alternatively, GenStar may begin with a predocked ‘inhibitor core’ from which atoms are grown. For each new atom generated by the program, several hundred candidate positions representing a range of reasonable bond lengths, bond angles, and torsion angles are considered. Each of these candidates is scored, based on a simple enzyme contact model. The selected position is chosen at random from among the highest scoring cases. Duplicate structures may be removed using a variety of criteria. The compounds may be energy minimized and displayed using standard modeling programs. Also, it is possible to analyze the collection of all structures created by GenStar and locate binding motifs for common fragments such as benzene and naphthylene. Tests of the method using HIV protease, FK506 binding protein (FKBP-12) and human carbonic anhydrase (HCA-II) demonstrated that structures similar to known potent inhibitors may be generated with GenStar.

Key words

Drug design Protein structure Drug-ligand interactions HIV protease inhibitors Carbonic anhydrase inhibitors Ligand design Protein active site Enzyme inhibitors FKBP-12 inhibitors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cohen, N.C., Blaney, J.M., Humblet, C., Gund, P. and Barry, D.C., J. Med. Chem., 22 (1990) 883.Google Scholar
  2. 2.
    Gund, P., Halgren, T.A. and Smith, G.M., Annu. Rep. Med. Chem., 22 (1987) 269.Google Scholar
  3. 3.
    Marshall, G.R., Annu. Rev. Pharmacol. Toxicol., 27 (1987) 193.Google Scholar
  4. 4.
    Frühbeis, H., Klein, R. and Wallmeier, H., Angew. Chem. Int. Ed. Engl., 26 (1987) 403.Google Scholar
  5. 5.
    Snyder, J.P., Med. Chem. Rev., 11 (1991) 641.Google Scholar
  6. 6.
    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.R., Kan, C.-C., Kathardekar, 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., Villafranca, J.E., Ward, R.W., Webber, S., Webber, S.E., Welsh, K.M. and White, J., J. Med. Chem., 34 (1991) 1925.Google Scholar
  7. 7.
    Baldwin, J.J., Ponticello, G.S., Anderson, P.S., Christy, M.E., Murcko, M.A., Randall, W.C., Schwam, H., Sugrue, M.F., Springer, J.P., Gautheron, P., Grove, J., Mallorga, P., Viader, M.-P., McKeever, B.M. and Navia, M.A., J. Med. Chem., 32 (1989) 2510.Google Scholar
  8. 8.
    Navia, M.A. and Murcko, M.A., Curr. Opin. Struct. Biol., 2 (1992) 202.Google Scholar
  9. 9.
    Fesik, S.W., J. Med. Chem., 34 (1991) 2937.Google Scholar
  10. 10.
    Brunger, A.T., Kuriyan, J. and Karplus, M., Science, 235 (1987) 458.Google Scholar
  11. 11.
    Argos, P. and Mohana Rao, J.K., Methods Enzymol., 30 (1986) 185.Google Scholar
  12. 12.
    Lathrop, R.H., Webster, T.A. and Smith, T.F., Comm. ACM, 30 (1987) 909.Google Scholar
  13. 13.
    Blundell, T.L., Sibanda, B.L., Sternberg, M.J.E. and Thornton, J.M., Nature, 326 (1987) 347.Google Scholar
  14. 14.
    Sander, C. and Schneider, R., Proteins Struct. Funct. Genet., 9 (1991) 56.Google Scholar
  15. 15.
    Kollman, P.A., In Horn, A.S. and Ranter, C.J.D. (Eds.), X-Ray Crystallography and Drug Action, Oxford University Press, London, 1984, pp. 63–82.Google Scholar
  16. 16.
    Dean, P.M., Molecular Foundations of Drug-Receptor Interaction, Cambridge University Press, Cambridge, 1987.Google Scholar
  17. 17.
    Fersht, A.R., Leatherbarrow, L.J. and Wells, T.N., Biochemistry, 26 (1987) 6030.Google Scholar
  18. 18.
    Quiocho, F.A., Wilson, D.K. and Vyas, N.K., Nature, 340 (1989) 404.Google Scholar
  19. 19.
    Sandorfy, C., Buchet, R., Hobza, P. and Ruelle, P., J. Mol. Struct. (Theochem), 107 (1984) 251.Google Scholar
  20. 20.
    Teeter, M.M. and Whitlow, M.D., Trans. ACA, 22 (1986) 75.Google Scholar
  21. 21.
    Zuccarello, F. and Del Re, G., J. Comp. Chem., 8 (1987) 816.Google Scholar
  22. 22.
    Tanford, C., The Hydrophobic Effect., 2nd edn., Wiley, New York, 1980.Google Scholar
  23. 23.
    Gill, S.J., Pure Appl. Chem., 61 (1989) 1009.Google Scholar
  24. 24.
    Lebl, M., Sugg, E.E. and Hruby, V.J., Int. J. Pept. Protein Res., 29 (1987) 40.Google Scholar
  25. 25.
    Homer, J. and Mohammadi, M.S., J. Chem. Soc. Faraday Trans. II, 83 (1987) 1957.Google Scholar
  26. 26.
    Burkert, U. and Allinger, N.L., In Molecular Mechanics (ACS Monograph Series, No. 177), American Chemical Society Press, Washington, 1982, pp. 39–52.Google Scholar
  27. 27.
    Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., J. Am. Chem. Soc., 112 (1990) 6127.Google Scholar
  28. 28.
    Arald, J.-C., Nicholls, A., Sharp, K., Honig, B., Tempczyk, A., Hendrickson, T.F. and Still, W.C., J. Am. Chem. Soc., 113 (1991) 1454.Google Scholar
  29. 29.
    Gilson, M.K. and Honig, B., J. Comput.-Aided Mol. Design, 5 (1991) 5.Google Scholar
  30. 30.
    Burley, S.K. and Petsko, G.A., Adv. Prot. Chem., 39 (1988) 125.Google Scholar
  31. 31.
    Thomas, K.A., Smith, G.M., Thomas, T.B. and Feldmann, R.J., Proc. Natl. Acad. Sci. USA, 79 (1982) 4843.Google Scholar
  32. 32.
    Náray-Szabó, G., J. Mol. Graphics, 7 (1989) 76.Google Scholar
  33. 33.
    Hayes, D.M. and Kollman, P.A., J. Am. Chem. Soc., 98 (1976) 3335.Google Scholar
  34. 34.
    Bellido, M.N. and Rullmann, J.A.C., J. Comput. Chem., 10 (1989) 479.Google Scholar
  35. 35.
    Goodford, P.J., J. Med. Chem., 28 (1985) 849.Google Scholar
  36. 36.
    Boobbyer, D.N.A., Goodford, P.J., McWhinnie, P.M. and Wade, R.C., J. Med. Chem., 32 (1989) 1083.Google Scholar
  37. 37.
    Danziger, D.J. and Dean, P.M., Proc. R. Soc. London Ser. B, Biol. Sci., 236 (1989) 101.Google Scholar
  38. 38.
    Danziger, D.J. and Dean, P.M., Proc. R. Soc. London Ser. B, Biol. Sci., 236 (1989) 115.Google Scholar
  39. 39.
    Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., J. Comput. Chem., 4 (1983) 187.Google Scholar
  40. 40.
    Miranker, A. and Karplus, M., Proteins Struct. Funct. Genet., 11 (1991) 29.Google Scholar
  41. 41.
    Goodsell, D.S. and Olsen, A.J., Proteins Struct. Funct. Genet., 8 (1990) 195.Google Scholar
  42. 42.
    Yue, S.-Y., Prot. Eng., 4 (1990) 177.Google Scholar
  43. 43.
    Wilson, S.R. and Guarneri, F., Tetrahedron Lett., 32 (1991) 3601.Google Scholar
  44. 44.
    Lee, R.H. and Rose, G.D., Biopolymers, 24 (1985) 1613.Google Scholar
  45. 45.
    Lesk, A.M., Acta Crystallogr., A42 (1986) 83.Google Scholar
  46. 46.
    Lewis, R.A. and Dean, P.M., Proc. R. Soc. London Ser. B, Biol. Sci., 236 (1989) 125.Google Scholar
  47. 47.
    Lewis, R.A., Dean, P.M., Proc. R. Soc. London Ser B, Biol. Sci., 236 (1989) 141.Google Scholar
  48. 48.
    Lewis, R.A., J. Comput.-Aided Mol. Design, 4 (1990) 205.Google Scholar
  49. 49.
    Lewis, R.A., Roe, D.C., Huang, C., Ferrin, T.E., Langridge, R. and Kuntz, I.D., J. Mol. Graphics, 10 (1992) 66.Google Scholar
  50. 50.
    Bartlett, P.A., Shea, G.T., Telfer, S.J. and Waterman, Spec. Publ., Royal Chem. Soc., 78 (1989) 182.Google Scholar
  51. 51.
    CAVEAT: A Program to Facilitate the Design of Organic Molecules. Lauri, G., Shea, G.T., Waterman, S., Telfer, S.J., Bartlett, P.A., Version 2.0, University of California at Berkeley.Google Scholar
  52. 52.
    Van Drie, J.H., Weininger, D. and Martin, Y.C., J. Comput.-Aided Mol. Design, 3 (1989) 225.Google Scholar
  53. 53.
    Martin, Y.C., Tetrahedron Comp. Methodol., 3 (1990) 15.Google Scholar
  54. 54.
    Sheridan, R.P., RusinkoIII, A., Nilakantan, R. and Venkataraghavan, R., Proc. Natl. Acad. Sci. USA, 86 (1989) 8165.Google Scholar
  55. 55.
    Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269Google Scholar
  56. 56.
    DesJarlais, R.L., Sheridan, R.P., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem., 29 (1986) 2149.Google Scholar
  57. 57.
    DesJarlais, R.L., Sheridan, R.P., Seibel, G.L., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem., 31 (1989) 722.Google Scholar
  58. 58.
    DesJarlais, R.L., Seibel, G.L., Kuntz, I.D., Furth, P.S., Alvarez, J.C., 87 De Montellano, P.R.O., DeCamp, D.L., Babé, L.M. and Craik, C.S., Proc. Natl. Acad. Sci. USA, (1990) 6644.Google Scholar
  59. 59.
    Lawrence, M.C. and Davis, P.C., Proteins Struct. Funct. Genet., 12 (1992) 31.Google Scholar
  60. 60.
    Bohm, H.-J., J. Comput.-Aided Mol. Design, (1992) 61.Google Scholar
  61. 61.
    Bernstein, F.C., Koetzle, T.F., Williams, G.T.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., (1977) 535.Google Scholar
  62. 62.
    Allen, F.H., Kennard, O. and Taylor, R., Acc. Chem. Res., 16 (1983) 146.Google Scholar
  63. 63.
    Nishibata, Y. and Itai, A., Tetrahedron, 47 (1991) 8985.Google Scholar
  64. 64.
    Singh, J., Saldanha, J. and Thornton, J.M., Prot. Eng., 4 (1991) 251.Google Scholar
  65. 65.
    Moon, J.B. and Howe, W.J., Proteins Struct. Funct. Genet., 11 (1991) 314.Google Scholar
  66. 66.
    Wiberg, K.B. and Murcko, M.A., J. Am. Chem. Soc., 110 (1988) 8029.Google Scholar
  67. 67.
    Yamashita, M.M., Wesson, L., Eisenman, G. and Eisenberg, D., Proc. Natl. Acad. Sci. USA, 87 (1990) 5648.Google Scholar
  68. 68.
    InsightII, version 2.1, Biosym Technologies, San Diego, CA.Google Scholar
  69. 69.
    Connoly, M.L., Science, 221 (1983) 709.Google Scholar
  70. 70.
    Perry, B.K. and Murcko, M.A., unpublished results.Google Scholar
  71. 71.
    Moore, J.M., Peattie, D.A., Fitzgibbon, M.J. and Thomson, J.A., Nature, 351 (1991) 248.Google Scholar
  72. 72.
    Van Duyne, G.D., Standaert, R.F., Karplus, P.A., Schreiber, S.L. and Clardy, J., Science, 252 (1991) 839.Google Scholar
  73. 73.
    Michnick, S.W., Rosen, M.K., Wandless, T.J., Karplus, M. and Schreiber, S.L., Science, 252 (1991) 836.Google Scholar
  74. 74.
    Van Duyne, G.D., Standaert, R.F., Schreiber, S.L. and Clardy, J., J. Am. Chem. Soc., 113 (1991) 7433.Google Scholar
  75. 75.
    CHARMM, version 21, Molecular Simulations, Waltham, MA.Google Scholar
  76. 76.
    Swain, A.L., Miller, M.M., Green, J., Rich, D.J., Schneider, J., Kent, S.B.H. and Wlodawer, A., Proc. Natl. Acad. Sci. USA, 87 (1990) 8805.Google Scholar
  77. 77.
    Roberts, N.A., Martin, J.A., Kinchington, D., Broadhurst, A.V., Craig, J.C., Duncan, I.B., Galpin, S.A., Handa, B.K., Kay, J., Krohn, A., Lambert, R.W., Merrett, J.H., Mills, J.S., Parkes, K.E.B., Redshaw, S., Ritchie, A.J., Taylor, D.A., Thomas, G.H. and Machin, P.J., Science, 248 (1990) 358.Google Scholar
  78. 78.
    Krohn, A., Redshaw, S., Ritchie, J.C., Graves, B.J. and Hatada, M.H., J. Med. Chem., 34 (1991) 3340.Google Scholar
  79. 79.
    Maren, T.H., Drug Dev. Res., 10 (1987) 255.Google Scholar
  80. 80.
    Eriksson, A.E., Jones, T.A. and Liljas, A., Proteins Struct. Funct. Genet., 4 (1988) 274.Google Scholar
  81. 81.
    Eriksson, A.E., Kylsten, P.M., Jones, T.A. and Liljas, A., Proteins Struct. Funct. Genet., 4 (1988) 283.Google Scholar
  82. 82.
    Merck & Company Annual Report, Rahway, NJ, 1990, p. 36.Google Scholar
  83. 83.
    Murcko, M.A., unpublished results.Google Scholar
  84. 84.
    Privalov, P.L. and Gill, S.J., Pure Appl. Chem., 61 (1989) 1097.Google Scholar
  85. 85.
    Privalov, P.L. and Gill, S.J., Adv. Prot. Chem., 39 (1988) 191.Google Scholar
  86. 86.
    KellisJr., J.T., Nyberg, K., Sali, D. and Fersht, A.R., Nature, 333 (1988) 784.Google Scholar
  87. 87.
    Rashin, A.A., Iofin, M. and Honig, B., Biochemistry, 25 (1986) 3619.Google Scholar
  88. 88.
    Eriksson, A.E., Baase, W.A., Zhang, X.-J., Heinz, D.W., Blaber, M., Baldwin, E.P. and Matthews, B.W., Science, 255 (1992) 178.Google Scholar
  89. 89.
    Reynolds, J.A., Gilbert, D.B. and Tanford, C., Proc. Natl. Acad. Sci. USA, 71 (1974) 2925.Google Scholar
  90. 90.
    Hermann, R.B., J. Phys. Chem., 76 (1972) 2754.Google Scholar
  91. 91.
    Sharp, K.A., Nicholls, A., Friedman, R. and Honig, B., Biochemistry, 30 (1991) 9686.Google Scholar
  92. 92.
    KellisJr., J.T., Nyberg, K., Sali, D. and Fersht, A.R., Nature, 333 (1988) 784.Google Scholar
  93. 93.
    Chothia, C., J. Mol. Biol., 105 (1976) 1.Google Scholar
  94. 94.
    Kellis, J.T., Nyberg, K. and Fersht, A.R., Biochemistry, 28 (1989) 4914.Google Scholar
  95. 95.
    Shortle, D., Stites, W.E. and Meeker, A.K., Biochemistry, 29 (1990) 8033.Google Scholar
  96. 96.
    Connelly, P.R. and Thomson, J.A., Proc. Natl. Acad. Sci. USA, 89 (1992) 4781.Google Scholar

Copyright information

© ESCOM Science Publishers B.V. 1993

Authors and Affiliations

  • Sergio H. Rotstein
    • 1
  • Mark A. Murcko
    • 1
  1. 1.Vertex Pharmaceuticals IncorporatedCambridgeU.S.A.

Personalised recommendations