The Castlemaine Project: Development of an AI-based Drug Design Support System

  • Edward E. Hodgkin
Part of the Topics in Molecular and Structural Biology book series (TMSB)


The Castlemaine project is a 2½ year (December 1989 to May 1992) industrial and academic collaborative research project sponsored by the Information Engineering Directorate of the Department of Trade and Industry, a follow-up to the Alvey programme of the 1980s. The goals of the project, inspired by the ideas of Smithers and his co-workers in Edinburgh,1 are:
  1. (1)

    To produce a domain-independent model of the design process and an associated knowledge-based design support system with an architecture which attempts to embody some of this model.

  2. (2)

    To produce a model specific to the domain of drug design.

  3. (3)

    To produce support systems for drug design.



Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Smithers, T., Conkie, A., Doheny, J., Logan, B. and Millington, K. (1989). Design as intelligent behaviour: an AI in design research programme. In Artificial Intelligence in Design, ed. Gero, J., Computational Mechanics Publications, Springer-Verlag, SouthamptonGoogle Scholar
  2. 2.
    Buck, P., Clarke, B., Lloyd, G., Poulter, K., Smithers, T., Tang, M. X., Tomes, N., Floyd, C. D. and Hodgkin, E. E. (1991). The Castlemaine Project: Development of an AI-based design support system. In Artificial Intelligence in Design ’91, ed. Gero, J., Butterworth-Heinemann, Oxford, pp. 583–601Google Scholar
  3. 3.
    Smithers, T., Tang, M. X., Tomes, N., Buck, P., Clarke, B., Lloyd, G., Poulter, K., Floyd, C. D. and Hodgkin, E. E. (1992). Development of a knowledge based design support system. Knowledge Based Systems, 5, 31–40CrossRefGoogle Scholar
  4. 4.
    Hodgkin, E. E. (1990). British Bio-technology employs CAMD approaches across research groups. Chem. Des. Automat. News, 5, No. 11, 12–17Google Scholar
  5. 5.
    Lewis, R. A. and Dean, P. M. (1989). Automated site-directed drug design: the formation of molecular templates in primary structure generation. Proc. Roy. Soc. Lond. B, 236, 141–162CrossRefGoogle Scholar
  6. 6.
    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). Structure-based design of non-peptide inhibitors specific for the human immunodeficiency virus 1 protease. Proc. Natl Acad. Sci. USA, 87, 6644–6648CrossRefGoogle Scholar
  7. 7.
    Stahle, L. and Wold, S. (1988). Multivariate data analysis and experimental design in biomedical research. Progr. Med. Chem., 25, 291–338CrossRefGoogle Scholar
  8. 8.
    Mayer, D., Naylor, C. B., Motoc, I. and Marshall, G. R. (1987). A unique active site geometry of angiotensin-converting enzyme consistent with structure-activity studies. J. Comp.-Aided Mol. Design, 1, 3–16CrossRefGoogle Scholar
  9. 9.
    Marshall, G. R., Mayer, D., Naylor, C. B., Hodgkin, E. E. and Cramer, R. D. III (1989). Mechanism-based analysis of enzyme inhibitors by amide bond hydrolysis. In QSAR: Quantitative Structure-Activity Relationships in Drug Design, ed. Fauchere, J., Alan R. Liss, New York, pp. 287–296Google Scholar
  10. 10.
    Hodgkin, E. E., Miller, A. and Whittaker, M. (1992). A partial pharmacophore for the platelet-activating factor (PAF) receptor. Bioorg. Med. Chem. Lett., 2, 597–602CrossRefGoogle Scholar
  11. 11.
    Cramer, R. D. III, Patterson, D. E. and Bunce, J. D. (1989). Comparative Molecular Field Analysis (CoMFA). In QSAR: Quantitative Structure-Activity Relationships, ed. Fauchere, J., Alan R. Liss, New York, pp. 161–165Google Scholar
  12. 12.
    Sheridan, R. P., Rusinko, A. III, Nilakantan, R. and Venkataraghavan, R. (1989). Searching for pharmacophores in large coordinate data bases and its use in drug design. Proc. Natl Acad. Sci. USA, 86, 8165–8169CrossRefGoogle Scholar
  13. 13.
    Baber, J. C. and Hodgkin, E. E. (1993). Automatic assignment of chemical connectivity to organic molecules in the Cambridge Structural Database. J. Chem. Inf. Comp. Sci. (in press)Google Scholar
  14. 14.
    Gold Hill Computers Inc. (1989). 26 Landsdowne Street, Cambridge, MA 02139, USAGoogle Scholar
  15. 15.
    Cooper, D. G., Young, R. C., Durant, G. J. and Ganellin, C. R. (1990). Histamine receptors. In Comprehensive Medicinal Chemistry, Vol. 3, ed. Hansch, C., Sammes, P. G., Taylor, J. B. and Emmett, J. C., Pergamon Press, Oxford, pp. 323–421Google Scholar
  16. 16.
    Main, B. G. (1990). β-Adrenergic receptors. In Comprehensive Medicinal Chemistry, Vol. 3, ed. Hansch, C., Sammes, P. G., Taylor, J. B. and Emmett, J. C., Pergamon Press, Oxford, pp. 187–228Google Scholar
  17. 17.
    Konzett, H. (1940). Neue broncholytisch hochwirksame korper der adrenalinreihe. Arch. Exp. Pathol. Pharmakol., 197, 27–40CrossRefGoogle Scholar
  18. 18.
    Engelhardt, A., Hoefke, W. and Wick, H. (1961). Zur pharmokologie des sympathomimeticums 1-(3,5-dihydroxyphenyl)-1-hydroxy-2-isopropyl-aminoathan. Arzneim.-Forsch., 11, 521–525Google Scholar
  19. 19.
    Kaiser, C., Colella, D. F., Schwartz, M. S., Garvey, E. and Wardell, J. R. (1974). Adrenergic agents. 1. Synthesis and potential β-adrenergic agonist activity of some catecholamine analogs bearing a substituted amino functionality in the meta position. J. Med. Chem., 17, 49–57CrossRefGoogle Scholar
  20. 20.
    Scriabine, A., Moore, P. F., Iorio, L. C., Goldman, I. M., McShane, W. K. and Booher, K. D. (1968). Quinterenol, a new beta adrenergic stimulant. J. Pharmacol. Exp. Ther., 162, 60–69Google Scholar
  21. 21.
    Yoshizaki, S., Tanimura, K., Tamada, S., Yabuuchi, Y. and Nakagawa, K. (1976). Sympathomimetic amines having a carbostyril nucleus. J. Med Chem., 19, 1138–1142CrossRefGoogle Scholar
  22. 22.
    Arnett, C. D., Wright, J. and Zenker, N. (1978). Synthesis and adrenergic activity of benzimidazole bioisosteres of norepinephrine and isoproterenol. J. Med. Chem., 21, 72–78CrossRefGoogle Scholar
  23. 23.
    Williams, H. W. R. (1976). Synthesis of some 4-pyranones and 4-pyridones structurally related to isoproterenol. Can. J. Chem., 54, 3377–3382CrossRefGoogle Scholar
  24. 24.
    DeVries, V. G., Bloom, J. D., Dutia, M. D., Katocs, A. S. and Largis, E. E. (1989). Potential antiatherosclerotic agents. 6. Hypocholesterolemic trisubstituted urea analogues. J. Med. Chem., 32, 2318–2325CrossRefGoogle Scholar
  25. 25.
    Thornber, C. W. (1979). Isosterism and molecular modification in drug design. Chem. Soc. Rev., 8, 563–580CrossRefGoogle Scholar
  26. 26.
    Hashiguchi, H. and Takahashi, H. (1977). Inhibition of two copper-containing enzymes, tyrosinase and dopamine β-hydrolase, by L-mimosine. Mol. Pharmacol., 13, 362–367Google Scholar
  27. 27.
    Norton, S. J. and Sanders, E. (1967). DL-4,5-Dihydroxy-2-pyridyl-alanine, an analog of 3,4-dihydroxyphenylalanine. J. Med. Chem., 10, 961–963CrossRefGoogle Scholar
  28. 28.
    Harris, R. L. N. and Teitei, T. (1977). Potential wool growth inhibitors. 2(1H)-pyridone analogues of mimosine. Aust. J. Chem., 30, 649–655CrossRefGoogle Scholar
  29. 29.
    Inouye, S., Shomura, T., Tsuruoka, T., Ogawa, Y., Watanabe, H., Yoshida, A. and Niida, T. (1975). L-β-(5-Hydroxy-2-pyridyl)-alanine and L-β-(3-hydroxyureido)-alanine from Streptomyces. Chem. Pharmacol. Bull., 23, 2669–2677CrossRefGoogle Scholar
  30. 30.
    Rich, E. (1988). Artificial Intelligence, McGraw-Hill, New YorkGoogle Scholar
  31. 31.
    Shadbolt, N. (1988). Knowledge elicitation: the key to successful ES. Expert Systems, 10, 22–25Google Scholar
  32. 32.
    Williams, N. and Holt, P. (1988). Expert Systems for Users, McGraw-Hill, New YorkGoogle Scholar
  33. 33.
    Burton, A. M., Shadbolt, N. R., Rugg, G. and Hedgecock, A. P. (1990). The efficacy of knowledge elicitation techniques: a comparison across domains and levels of expertise. Knowledge Acquisition, 2, 167–178CrossRefGoogle Scholar
  34. 34.
    Maher, M. L. (1990). Process model for design synthesis. AI Magazine, Winter, 49–58Google Scholar
  35. 35.
    Dasgupta, S. (1989). The structure of the design process. Adv. Comp., 28, 1–67CrossRefGoogle Scholar

Copyright information

© J. G. Vinter and M. Gardner 1994

Authors and Affiliations

  • Edward E. Hodgkin

There are no affiliations available

Personalised recommendations