Skip to main content
SpringerLink
Log in

Challenges and prospects for computational aids to molecular diversity

  • Published:
Perspectives in Drug Discovery and Design

Summary

Although workers have devised many usable strategies, a validated method for the computational analysis and optimization of molecular diversity in compound collections or combinatorial libraries remains a challenge. Even the most ambitious programs consider less than 1:1039 of all possible compounds. The various methods need to be validated against experimental data and compared with each other, which might require sharing the structures and biological activities of 105–106 molecules. We need molecular descriptors that more accurately reflect the biological properties of compounds: this will probably entail designing a strategy to realistically include the properties of the multiple conformers, tautomers, and ionization states of molecules. For true computer generation of diverse synthesizable compounds, we need a whole new generation of programs that organize the knowledge of synthetic organic chemistry. Additionally, if the goal is to design molecules to fit a macromolecular target of known 3D structure, we also need improved methods for estimating ligand affinity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Czarnik, A.W., Chemtracts-Org. Chem., 8 (1995) 13.

    CAS  Google Scholar 

  2. Available Chemicals Directory, MDL Information Systems Inc., San Leandro, CA, 1997.

  3. Siani, M.A., Weininger, D. and Blaney, J.M., J. Chem. Inf. Comput. Sci., 34 (1994) 588.

    Article  CAS  PubMed  Google Scholar 

  4. Siani, M.A., Weininger, D., James, C.A. and Blaney, J.M., J. Chem. Inf. Comput. Sci., 35 (1995) 1026.

    Article  CAS  PubMed  Google Scholar 

  5. Pearlman, R., Combindbmaker, University of Texas, Austin, TX, 1996.

    Google Scholar 

  6. Legion and Unity, Tripos Inc., St. Louis, MO, 1997.

  7. Project Library and Central Library, MDL Information Systems Inc., San Leandro, CA, 1997.

  8. Chem-X, Chemical Design Ltd., Oxon, 1996.

  9. Merlin and Thor, Daylight Chemical Information Systems Inc., Mission Viejo, CA, 1997.

  10. Warr, W., Perspect. Drug Discov. Design, 7/8 (1997) 115 (this issue).

    CAS  Google Scholar 

  11. Downs, G.M. and Barnard, J.M., J. Chem. Inf. Comput. Sci., 37 (1997) 59.

    Article  CAS  Google Scholar 

  12. ChemSpace and SpaceCrunch, Tripos Inc., St. Louis, MO, http://www.tripos.com/spacecrunch/ChemSpace.html, 1996.

  13. Brown, R.D., Perspect. Drug Discov. Design, 7/8 (1997) 31 (this issue).

    CAS  Google Scholar 

  14. Strynadka, N., Eisenstein, M., Katchalskikatzir, E., Shoichet, B.K., Kuntz, I.D., Abagyan, R., Totrov, M., Janin, J., Cherfils, J., Zimmerman, F., Olson, A., Duncan, B., Rao, M., Jackson, R., Sternberg, M. and James, M., Nat. Struct. Biol., 3 (1996) 233.

    Article  CAS  PubMed  Google Scholar 

  15. Brown, R.D. and Martin, Y.C., J. Chem. Inf. Comput. Sci., 37 (1997) 1.

    Article  CAS  Google Scholar 

  16. Martin, Y.C., Brown, R.D., Lico, I. and Delazzer, J., Submitted to Internet Journal of Chemistry.

  17. Anzali, S., Barnickel, G., Krug, M., Sadowski, J., Wagener, M., Gasteiger, J. and Polanski, J., J. Comput.-Aided Mol. Design, 10 (1996) 521.

    Article  CAS  Google Scholar 

  18. Nilakantan, R., Bauman, N. and Venkataraghavan, R., J. Chem. Inf. Comput. Sci., 33 (1993) 79.

    Article  CAS  PubMed  Google Scholar 

  19. Bemis, G.W. and Kuntz, I.D.A., J. Comput.-Aided Mol. Design, 6 (1992) 607.

    Article  CAS  Google Scholar 

  20. Good, A.C. and Richards, W.G., J. Chem. Inf. Comput. Sci., 33 (1993) 112.

    Article  CAS  Google Scholar 

  21. Meyer, A.M. and Richards, W.G., J. Comput.-Aided Mol. Design, 5 (1991) 426.

    Article  Google Scholar 

  22. Bath, P.A., Poirrette, A.R. and Willett, P., J. Chem. Inf. Comput. Sci., 35 (1995) 714.

    Article  CAS  Google Scholar 

  23. Bath, P.A., Poirette, A.R., Willett, P. and Allen, F.H., J. Chem. Inf. Comput. Sci., 34 (1994) 141.

    Article  CAS  Google Scholar 

  24. Bures, M., unpublished observations, 1997.

  25. Willett, P., Similarity and Clustering Techniques in Chemical Information Systems, Research Studies Press, Letchworth, 1987.

    Google Scholar 

  26. Brown, R.D. and Martin, Y.C., J. Chem. Inf. Comput. Sci., 36 (1996) 572.

    Article  CAS  Google Scholar 

  27. Patterson, D.E., Cramer, R.D., Ferguson, A.M., Clark, R.D. and Weinberger, L.E., J. Med. Chem., 39 (1996) 3049.

    Article  CAS  PubMed  Google Scholar 

  28. Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, 1993.

    Google Scholar 

  29. Martin, Y.C., Kim, K.-H. and Lin, C.T., In Charton, M. (Ed.) Advances in Quantitative Structure Property Relationships, JAI Press, Greenwich, CT, 1996, p. 1–52.

    Chapter  Google Scholar 

  30. Kuntz, I.D., Science, 257 (1992) 1078.

    Article  CAS  PubMed  Google Scholar 

  31. Wang, S.M., Milne, G.W.A., Yan, X.J., Posey, I.J., Nicklaus, M.C., Graham, L. and Rice, W.G., J. Med. Chem., 39 (1996) 2047.

    Article  CAS  PubMed  Google Scholar 

  32. Mason, J.S., McLay, I.M. and Lewis, R.A., In Dean, P.M., Jolies, G. and Newton, C.G. (Eds.) New Perspectives in Drug Design, Academic Press, London, 1995, p. 225–253.

    Google Scholar 

  33. Martin, Y.C., J. Med. Chem., 35 (1992) 2145.

    Article  CAS  PubMed  Google Scholar 

  34. Raevsky, O.A., Grigor’ev, V.J., Kireev, D.B. and Zefirov, N.S., Quant. Struct.-Act. Relatsh., 11 (1992) 49.

    Article  Google Scholar 

  35. Abraham, M.H., Duce, P.P., Prior, D.V., Garratt, D.G., Morris, J.J. and Taylor, P.J., J. Chem. Soc., Perkin Trans. 2, (1989) 1355.

    Article  Google Scholar 

  36. Burres, N.S. and Clement, J.J., In Zambias, R. and Kolb, A. (Eds.) American Chemical Society, Washington, DC, 1997, in press.

  37. Martin, Y.C., Brown, R.D. and Bures, M.G., In Kerwin, J.F. and Gordon, E.M. (Eds.) Combinatorial Chemistry and Molecular Diversity, Wiley, New York, NY, 1997, in press.

    Google Scholar 

  38. Taylor, R., J. Chem. Inf. Comput. Sci., 35 (1995) 59.

    Article  CAS  Google Scholar 

  39. Brown, R.D. and Martin, Y.C., J. Med. Chem., 40 (1997) 2304.

    Article  CAS  PubMed  Google Scholar 

  40. Downs, G.M., Willett, P. and Fisanick, W., J. Chem. Inf. Comput. Sci., 34 (1994) 1094.

    Article  CAS  Google Scholar 

  41. Pearlman, R.S., Network Science, http://www.awod.com/netsci/Issues/, June 1996.

  42. Gordon, E.M., Gallop, M.A. and Patel, D.V., Acc. Chem. Res., 29 (1996) 144.

    Article  CAS  Google Scholar 

  43. Choong, I.C. and Ellman, J.A., In Bristol, J.A. (Ed.) Annual Reports in Medicinal Chemistry, Academic Press, San Diego, CA, 1996, p. 309–318.

    Google Scholar 

  44. Gasteiger, J., Ihlenfeldt, W.-D., Fick, R. and Rose, J.R., J. Chem. Inf. Comput. Sci., 32 (1992) 700.

    Article  CAS  Google Scholar 

  45. Weber, L., Wallbaum, S., Broger, C. and Gubernator, K., Angew. Chem., Int. Ed. Engl., 34 (1995) 2280.

    Article  CAS  Google Scholar 

  46. Singh, J., Ator, M.A., Jaeger, E.P., Allen, M.P., Whipple, D.A., Soloweij, J.E., Chowdhary, S. and Treasurywala, A.M., J. Am. Chem. Soc., 118 (1996) 1669.

    Article  CAS  Google Scholar 

  47. Boyd, D.B., In Lipkowitz, K.B. and Boyd, D.B. (Eds.) Reviews in Computational Chemistry, VCH, New York, NY, 1990, p. 355–371.

    Chapter  Google Scholar 

  48. Hansch, C. and Leo, A., Exploring QSAR: Fundamentals and Applications in Chemistry and Biology, American Chemical Society, Washington, DC, 1995.

    Google Scholar 

  49. Martin, Y.C., Quantitative Drug Design, Marcel Dekker, New York, NY, 1978.

    Google Scholar 

  50. DeWitt, S.H., Kiely, J.S., Stankovic, C.J., Schroeder, M.C., Cody, D.M.R. and Pavia, M.R., Proc. Natl. Acad. Sci. USA, 90 (1993) 6909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gombar, V.K. and Enslein, K., J. Chem. Inf. Comput. Sci., 36 (1996) 1127.

    Article  CAS  PubMed  Google Scholar 

  52. Klopman, G. and Li, J.-Y., J. Comput.-Aided Mol. Design, 9 (1995) 283.

    Article  CAS  Google Scholar 

  53. Klopman, G., J. Am. Chem. Soc., 106 (1984) 7315.

    Article  CAS  Google Scholar 

  54. Sheridan, R.P., Miller, M.D., Underwood, D.J. and Kearsley, S.K., J. Chem. Inf. Comput. Sci., 36 (1996) 128.

    Article  CAS  Google Scholar 

  55. Kearsley, S.K., Sallamack, S., Fluder, E.M., Andose, J.D., Mosley, R.T. and Sheridan, R.P., J. Chem. Inf. Comput. Sci., 36 (1996) 118.

    Article  CAS  Google Scholar 

  56. Sheridan, R.P. and Kearsley, S.K., J. Chem. Inf. Comput. Sci., 35 (1995) 310.

    Article  CAS  Google Scholar 

  57. Agrafiotis, D.K., Bone, R.F., Saleme, F.R. and Soll, R.M., USA Patent no. 5,463,564, October 31, 1995.

  58. Martin, Y.C., In Martin, Y.C. and Willett, P. (Eds.) Design of Bioactive Molecules Using 3D Structural Information, American Chemical Society, Washington, DC, 1997, in press.

    Google Scholar 

  59. Willett, P., J. Mol. Recog., 8 (1995) 290.

    Article  CAS  Google Scholar 

  60. Brookhaven National Laboratory, Brookhaven, NY, http://www.pdb.bnl.gov/, 1997.

  61. Kick, E.K., Roe, D.C., Skillman, A.G., Liu, G., Weing, T., Sun, Y., Kuntz, I.D. and Ellman, J., Chem. Biol., 4 (1997) 297.

    Article  CAS  PubMed  Google Scholar 

  62. Dixon, S. and Blaney, J., In Martin, Y.C. and Willett, P., (Eds.) Design of Bioactive Molecules Using 3D Structural Information, American Chemical Society, Washington, DC, 1997, in press.

    Google Scholar 

  63. Böhm, H.J., J. Comput.-Aided Mol. Design, 10 (1996) 265.

    Article  Google Scholar 

  64. Gillet, V.J. and Johnson, A.P., In Martin, Y.C. and Willett, P. (Eds.) Design of Bioactive Molecules Using 3D Structural Information, American Chemical Society, Washington, DC, 1997, in press.

    Google Scholar 

  65. Ott, M.A. and Noordik, J.H., Recl. Trav. Chim. Pays-Bas, 111 (1992) 239.

    Article  CAS  Google Scholar 

  66. Gasteiger, J., Ihlenfeldt, W.-D. and Röse, P., Recl. Trav. Chim. Pays-Bas, 111 (1992) 270.

    Article  CAS  Google Scholar 

  67. MDL Information Systems Inc., San Leandro, CA, 1997.

  68. CrossFire, Beilstein Informationssysteme GmbH, Frankfurt, 1995.

  69. Moll, R., J. Chem. Inf. Comput. Sci., 37 (1997) 131.

    Article  CAS  Google Scholar 

  70. Pensak, D.A. and Corey, E.J., In (Eds.) Computer assisted Organic Synthesis, American Chemical Society, Washington, DC, 1977, pp. 1–32.

    Book  Google Scholar 

  71. Wipke, W.T. and Rogers, D., J. Chem. Inf. Comput. Sci., 24 (1984) 71.

    Article  CAS  PubMed  Google Scholar 

  72. Johnson, A.P., Marshall, C. and Judson, P.N., J. Chem. Inf. Comput. Sci., 32 (1992) 411.

    Article  CAS  Google Scholar 

  73. Corey, E.J., Long, E.K., Lotto, G.I. and Rubenstein, S.D., Recl. Trav. Chim. Pays-Bas, 111 (1992) 304.

    Article  CAS  Google Scholar 

  74. Ihlenfeldt, W.-D. and Gasteiger, J., Angew. Chem., Int. Ed. Engl., 34 (1995) 2613.

    Article  CAS  Google Scholar 

  75. Caflisch, A. and Karplus, M., Perspect. Drug Discov. Design, 3 (1995) 51.

    Article  CAS  Google Scholar 

  76. Cosgrove, D.A. and Kenny, P.W., J. Mol. Graph., 14 (1996) 1.

    Article  CAS  PubMed  Google Scholar 

  77. Welch, W., Ruppert, J. and Jain, A.N., Chem. Biol., 3 (1996) 449.

    Article  CAS  PubMed  Google Scholar 

  78. Shuker, S., Hajduk, P., Meadows, R. and Fesik, S., Science, 274 (1996) 1531.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. D-47E, AP10/2, Pharmaceutical Products Discovery, 100 Abbott Park Road, Abbott Park, IL, 60064-3500, USA

    Yvonne Connolly Martin

Authors
  1. Yvonne Connolly Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin, Y.C. Challenges and prospects for computational aids to molecular diversity. Perspectives in Drug Discovery and Design 7, 159–172 (1996). https://doi.org/10.1007/BF03380186

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03380186

Search

Navigation