Multiple computer-automated structure evaluation model of the plasma protein binding affinity of diverse drugs


A drug protein binding model was constructed on the basis of protein-affinity data for154 drugs. The Multiple Computer-Automated Structure Evaluation program (M-CASE) was used for the construction of the model, which separates the total data set into groups of drugs with common structural features. For each of these groups, a multiparameter Quantitative Structure–Activity Relationship (QSAR) was obtained. The most general structural fragment for all investigated drugs is a part of the phenyl ring. The lipophilicity represented by the octanol–water partition coefficient was also found to be a significant parameter for each local QSAR. The model was shown to be able to predict correctly the percentage of drug bound in plasma for ∼80% of compounds with an average error of only ∼14%.


  1. 1.

    Reidenberg, M.M. and Erill, S. (Eds.) Drug—protein binding, Praeger, New York, NY, 1986.

    Google Scholar 

  2. 2.

    Fehske, K.J., Schläfer, U., Wollert, U. and Müller, W.E., Mol. Pharmacol., 21 (1982) 387.

    PubMed  CAS  Google Scholar 

  3. 3.

    Fehske, K.J., Müller, W.E. and Wollert, U., Biochem. Pharmacol., 30 (1981) 687.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Wanwimolruk, S., Birkett, D.J. and Brooks, P.M., Mol. Pharmacol., 24 (1983) 458.

    PubMed  CAS  Google Scholar 

  5. 5.

    Kragh-Hansen, U., Pharmacol. Rev., 33 (1981) 17.

    PubMed  CAS  Google Scholar 

  6. 6.

    Kosa, T., Maruyama, T. and Otagiri, M., Pharm. Res., 14 (1997) 1607.

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Hashimoto, S., Yabusaki, T., Takeuchi, H. and Harada, I., Biospectroscopy, 1 (1995) 375.

    CAS  Article  Google Scholar 

  8. 8.

    Maruyama, T., Otagiri, M. and Takadate, A., Chem. Pharm. Bull., 38 (1990) 1688.

    PubMed  CAS  Google Scholar 

  9. 9.

    Kremer, J.M.H., Pharmacol. Rev., 40 (1988) 1.

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Hervé, F., Duche, J.C., D'Athis, P., Marche, C., Barre, J. and Tillement, J.P., Pharmacogenetics, 6 (1996) 403.

    PubMed  Google Scholar 

  11. 11.

    Rahman, M.H., Miyoshi, T., Sukimoto, K., Takadate, A. and Otagiri, M., J. Pharmacobio-Dyn., 15 (1992) 7.

    PubMed  CAS  Google Scholar 

  12. 12.

    Imamura, H., Maruyama, T. and Otagiri, M., Biol. Pharm. Bull., 16 (1993) 926.

    PubMed  CAS  Google Scholar 

  13. 13.

    Hervé, F., Caron, G., Duché, J.C., Gaillard, P., Rahman, N.A., Tsantili-Kakoulidou, A., Carrupt, P.-A., D'Athis, P., Tillement, J.P. and Testa, B., Mol. Pharmacol., 54 (1998) 129.

    PubMed  Google Scholar 

  14. 14.

    Goodman Gilman, A., Goodman, L.S., Rall, T.W. and Murad, F. (Eds.), The Pharmacological Basis of Therapeutics, 7th ed., Macmillan, New York, NY, 1985.

    Google Scholar 

  15. 15.

    Piafsky, K.M. and Borgå , O., Clin. Pharmacol. Ther., 22 (1977) 545.

    PubMed  CAS  Google Scholar 

  16. 16.

    Weininger, D., J. Chem. Inf. Comput. Sci., 28 (1988) 31.

    CAS  Article  Google Scholar 

  17. 17.

    M-CASE, MULTICASE Inc., Cleveland, OH (, 1998.

  18. 18.

    Klopman, G., Li, J.-U., Wang, S. and Dimayuga, M., J. Chem. Inf. Comput. Sci., 34 (1994) 752.

    CAS  Article  Google Scholar 

  19. 19.

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

    CAS  Article  Google Scholar 

  20. 20.

    Klopman, G., J. Chem. Inf. Comput. Sci., 38 (1998) 78.

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Klopman, G., Quant. Struct.—Act. Relat., 11 (1992) 176.

    CAS  Google Scholar 

  22. 22.

    Parr, R.G. and Pearson, R.G., J. Am. Chem. Soc., 105 (1983) 7512.

    CAS  Article  Google Scholar 

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Saiakhov, R.D., Stefan, L.R. & Klopman, G. Multiple computer-automated structure evaluation model of the plasma protein binding affinity of diverse drugs. Perspectives in Drug Discovery and Design 19, 133–155 (2000).

Download citation

  • binding site
  • drug
  • lipophilicity
  • M-CASE
  • plasma protein binding