Journal of Computer-Aided Molecular Design

, Volume 13, Issue 1, pp 1–10 | Cite as

Comparative Molecular Similarity Index Analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries

  • Gerhard Klebe
  • Ute Abraham


Comparative molecular field analysis has been applied to a data set of thermolysin inhibitors. Fields expressed in terms of molecular similarity indices (CoMSIA) have been used instead of the usually applied Lennard-Jones- and Coulomb-type potentials (CoMFA). Five different properties, assumed to cover the major contributions responsible for ligand binding, have been considered: steric, electrostatic, hydrophobic, and hydrogen-bond donor or acceptor properties. The statistical evaluation of the field properties by PLS analysis reveals a similar predictive potential to CoMFA. However, significantly improved and easily interpretable contour maps are obtained. The features in these maps intuitively suggest where to modify a molecular structure in terms of physicochemical properties and functional groups in order to improve its binding affinity. They can also be interpreted with respect to the known structural protein environment of thermolysin. Most of the highlighted regions in the maps are mirrored by features in the surrounding environment required for binding. Using the derived correlation model, different members of a combinatorial library designed for thermolysin inhibition have been scored for affinity. The results obtained demonstrate the prediction power of the CoMSIA method.

comparative molecular field analysis contribution map interpretation molecular similarity thermolysin inhibition 3D QSAR 


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  1. 1.
    Müller, K., Perspect. Drug Discov. Design, 3 (1995) 1.Google Scholar
  2. 2.
    Cramer III, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.Google Scholar
  3. 3.
    Thibaut, U., In Kubinyi, H. (Ed.), 3D QSAR in Drug Design, ESCOM, Leiden, 1993, pp. 661–696.Google Scholar
  4. 4.
    Klebe, G., Abraham, U. and Mietzner, T., J. Med. Chem., 37 (1994) 4130.Google Scholar
  5. 5.
    Folkers, G., Merz, A. and Rognan, D., In Kubinyi, H. (Ed.), 3D QSAR in Drug Design, ESCOM, Leiden, 1993, pp. 583–618.Google Scholar
  6. 6.
    Stahle, L. and Wold, S., Prog. Med. Chem., 25 (1988) 292.Google Scholar
  7. 7.
    Cramer III, R.D., De Priest, S.A., Patterson, D.E. and Hecht, P., In Kubinyi, H. (Ed.), 3D QSAR in Drug Design, ESCOM, Leiden, 1993, pp. 443–485.Google Scholar
  8. 8.
    DePriest, S.A., Mayer, D.C.B. and Marshall, G.R., J. Am. Chem. Soc., 115 (1993) 5372.Google Scholar
  9. 9.
    Campbell, D.A., Bermate, J.C., Burkoth, T.S. and Patel, D.V., J. Am. Chem. Soc., 117 (1995) 5381.Google Scholar
  10. 10.
    Martin, Y.C., Bures, M.G., Danaher, E.A., De Lazzer, J., Lico, I. and Pavlik, P., J. Comput.-Aided Mol. Design, 7 (1993) 83.Google Scholar
  11. 11.
    Program DISCO is available from Tripos Ass., St. Louis, MO, USA.Google Scholar
  12. 12.
    Allen, F.H., Kennard, O. and Taylor, R., Acc. Chem. Res., 16 (1983) 146.Google Scholar
  13. 13.
    Klebe, G., J. Mol. Biol., 237 (1994) 212.Google Scholar
  14. 14.
    Dewar, M.J.S., Zoebisch, E.G., Healy, E.F. and Stewart, J.J.P., J. Am. Chem. Soc., 107 (1985) 3902.Google Scholar
  15. 15.
    Viswanadhan, V.N., Ghose, A.K., Revankar, G.R. and Robins, R.K., J. Chem. Inf. Comput. Sci., 29 (1989) 163.Google Scholar
  16. 16.
    Sybyl Molecular Modeling System (Version 6.1), Tripos Ass., St. Louis,MO, USA.Google Scholar
  17. 17.
    Kearsley, S.K. and Smith, G.M., Tetrahed. Comput. Meth., 3 (1990) 615.Google Scholar
  18. 18.
    Klebe, G., Mietzner, T. and Weber, F., J. Comput.-Aided Mol. Design, 8 (1994) 751.Google Scholar
  19. 19.
    Bartlett, P.A. and Marlowe, C.K., Biochemistry, 26 (1987) 8553.Google Scholar
  20. 20.
    Morihara, K. and Tsuzuki, H., Eur. J. Biochem., 15 (1970) 374.Google Scholar
  21. 21.
    We have to admit that is hardly possible to document by blackand-white drawings the graphical advantage of the CoMSIA maps that become obvious using an interactive computer terminal.Google Scholar
  22. 22.
    Morgan, B.P., Scholtz, J.M., Ballinger, M.D., Zipkin, I.D. and Bartlett, P.A., J. Am. Chem. Soc., 113 (1991) 297.Google Scholar
  23. 23.
    Tronrud, D.H., Holden, H.M. and Matthews, B.W., Science, 235 (1987) 571.Google Scholar
  24. 24.
    Bartlett, P.A. and Marlowe, C.K., Science, 235 (1987) 569.Google Scholar
  25. 25.
    Bash, U.C., Singh, P.A., Brown, F.K., Langridge, R. and Kollman, P.A., Science, 235 (1987) 574.Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Gerhard Klebe
    • 1
  • Ute Abraham
    • 2
  1. 1.Institute of Pharmaceutical Chemistry, University of MarburgMarbacher Weg 6Germany
  2. 2.BASF AG, Main LaboratoryLudwigshafenGermany

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