Perspectives in Drug Discovery and Design

, Volume 1, Issue 2, pp 321–328 | Cite as

Why are binding-site models more complicated than molecules?

  • G. M. Crippen
  • M. P. Bradley
  • W. W. Richardson
Perspectives Part II. Molecular Modeling


A commonly occurring problem in drug development is that the binding affinities for a few compounds to a particular binding site on some protein have been measured, but the crystal structure for that protein is not available. Quantitative structure-activity methods attempt to empirically correlate the binding data with various features of the chemical structures of the drug molecules, so that one can predict the binding of novel compounds and thus aid the search for improved drugs. A common feature of nearly all these methods, however, is that they rely—implicitly or explicitly—on a guess as to the positioning of each molecule when bound to the common site. If one instead assumes that each molecule is free to seek out its optimal positioning in the site, then correlating the observed activity to molecular structure becomes more difficult, and can lead to surprisingly complicated site models. Here we show with some extremely simple artificial examples how this complexity necessarily arises.

Key words

Quantitative structure-activity relations Voronoi diagrams Receptor-site mapping Pharmacophore 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Roberts, G.C.K., Feeney, J., Burgen, A.S.V. and Daluge, S., FEBS Lett., 131 (1981) 85.Google Scholar
  2. 2.
    Crippen, G.M., J. Med. Chem., 22 (1979) 988.Google Scholar
  3. 3.
    Ghose, A.K. and Crippen, G.M., J. Med. Chem., 28 (1985) 333.Google Scholar
  4. 4.
    Crippen, G.M., J. Comput. Chem., 8 (1987) 943.Google Scholar
  5. 5.
    Crippen, G.M. and Havel, T.F., Distance Geometry and Molecular Conformation, Research Studies Press Ltd. (Wiley), 1988.Google Scholar
  6. 6.
    Ghose, A.K. and Crippen, G.M., In Ramsden, C. (Ed.) Comprehensive Medicinal Chemistry: The Rational Design, Mechanistic Study, and Therapeutic Application of Chemical Compounds, Vol. 4, Pergamon Press, Oxford, 1990, pp. 715–733.Google Scholar
  7. 7.
    Boulu, L.G. and Crippen, G.M., J. Comput. Chem., 10 (1989) 673.Google Scholar
  8. 8.
    Boulu, L.G., Crippen, G.M., Barton, H.A., Kwon, H. and Marletta, M.A., J. Med. Chem., 33 (1990) 771.Google Scholar
  9. 9.
    Bradley, M.P. and Crippen, G.M., J. Med. Chem., 36 (1993) 3171.Google Scholar
  10. 10.
    Srivastava, S. and Crippen, G.M., J. Med. Chem., 1993, in press.Google Scholar
  11. 11.
    Ghose, A.K., Pritchett, A. and Crippen, G.M., J. Comput. Chem., 9 (1988) 80.Google Scholar
  12. 12.
    Viswanadhan, V.N., Ghose, A.K., Revankar, G.R. and Robins, R.K., J. Chem. Inf. Comput. Sci., 29 (1989) 163.Google Scholar

Copyright information

© ESCOM Science Publishers B.V. 1993

Authors and Affiliations

  • G. M. Crippen
    • 1
  • M. P. Bradley
    • 1
  • W. W. Richardson
    • 1
  1. 1.College of PharmacyUniversity of MichiganAnn ArborUSA

Personalised recommendations