Applications of free energy derivatives to analog design


Free energy derivatives, which were first used to analyze the sensitivity and the convergence of free energy calculations, have recently been proposed for use in analog design. In this article, we review the published applications of free energy derivatives to analog design, discuss the possible reasons for the success and failure of such applications, and describe our recent study on an alternative use of free energy derivatives in analog design. It is too early to definitively evaluate the usefulness of the free energy derivative method to yield valuable insights into analog design. Our recent study suggests that free energy derivatives hold promise in evaluating possible different binding sites for a given ligand and suggesting the sites of a ligand that are not suitable for further structural modifications.

This is a preview of subscription content, access via your institution.


  1. 1

    Beveridge, D.L. and DiCapua, F.M., Annu. Rev. Biophys. Biophys. Chem., 18 (1989) 431.

    Google Scholar 

  2. 2

    Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz K.M., Jr., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W. and Kollman, P.A., J. Am. Chem. Soc., 117 (1995) 5179.

    Google Scholar 

  3. 3

    Wong, C.F., J. Am. Chem. Soc., 113 (1991) 3208.

    Google Scholar 

  4. 4

    Wong, C.F. and Rabitz, H., J. Phys. Chem., 95 (1991) 9628.

    Google Scholar 

  5. 5

    Pearlman, D.A., J. Chem. Phys., 98 (1993) 8946.

    Google Scholar 

  6. 6

    Pearlman, D.A., J. Comput. Chem., 15 (1994) 105.

    Google Scholar 

  7. 7

    Gerber, P.R., Mark, A.E. and Van Gunsteren, W.F., J. Comput.-Aided Mol. Design, 7 (1993) 305.

    Google Scholar 

  8. 8

    Cieplak, P., Pearlman, D.A. and Kollman, P.A., J. Chem. Phys., 101 (1994) 627.

    Google Scholar 

  9. 9

    Cieplak, P. and Kollman, P.A., J. Mol. Recognition, (1995) manuscript submitted for publication.

  10. 10

    Smith, P.E. and Van Gunsteren, W.F., J. Chem. Phys., 100 (1994) 577.

    Google Scholar 

  11. 11

    Farlow, M., Gracon, S.I., Hershey, L.A., Lewis, K.W., Sadowsky, C.H. and Dolan-Ureno, J., J. Am. Med. Assoc., 268 (1992) 2523.

    Google Scholar 

  12. 12

    Sussman, J.L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L. and Silman, I., Science, 253 (1991) 872.

    Google Scholar 

  13. 13

    Harel, M., Schalk, I., Ehretsabatier, L., Bouet, F., Goeldner, M., Hirth, C., Axelsen, P.H., Silman, I. and Sussman, J.L., Proc. Natl. Acad. Sci. USA, 90 (1993) 9031.

    Google Scholar 

  14. 14

    Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided Mol. Design, 8 (1994) 669.

    Google Scholar 

  15. 15

    Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.S., Cheatham III, T.E., Debolt, S., Ferguson, D., Seibel, G. and Kollman, P.A., Comput. Phys. Lett., in press.

  16. 16

    Bayly, C.I., Cieplak, P., Cornell, W.D. and Kollman, P.A., J. Phys. Chem., 97 (1993) 10269.

    Google Scholar 

  17. 17

    Cornell, W.D., Cieplak, P., Bayly, C.I. and Kollman, P.A., J. Am. Chem. Soc., 115 (1993) 9620.

    Google Scholar 

  18. 18

    Van Eerden, J., Harkema, S. and Feil, D., J. Phys. Chem., 92 (1988) 5076.

    Google Scholar 

  19. 19

    Izatt, R.M., Terry, R.E., Haymore, B.L., Hansen, L.D., Dalley, N.K., Avondett, A.G. and Christensen, J.J., J. Am. Chem. Soc., 98 (1976) 7620.

    Google Scholar 

  20. 20

    Shutske, G.M., Pierrat, F.A., Cornfeldt, M.L., Szewczak, M.R., Huger, F.P., Bores, G.M., Haroutunian, V. and Davis, K.L., J. Med. Chem., 31 (1988) 1278.

    Google Scholar 

  21. 21

    Steinberg, G.M., Mednick, M.L., Maddox, J. and Rice, R., J. Med. Chem., 18 (1975) 1057.

    Google Scholar 

  22. 22

    Caldwell, J.W. and Kollman, P.A., J. Am. Chem. Soc., 117 (1995) 4177.

    Google Scholar 

  23. 23

    Chipot, C., Pearlman, D.A., Maigret, B. and Kollman, P.A., J. Am. Chem. Soc., (1995) manuscript submitted for publication.

Download references

Author information



Corresponding author

Correspondence to Peter A. Kollman.

Additional information

On sabbatical leave from: Neurochemistry Research, Mayo Foundation for Medical Education and Research, 4500 San Pablo Road, Jacksonville, FL 32224, U.S.A.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pang, YP., Kollman, P.A. Applications of free energy derivatives to analog design. Perspectives in Drug Discovery and Design 3, 106–122 (1995).

Download citation


  • Polymer
  • Free Energy
  • Valuable Insight
  • Structural Modification
  • Energy Calculation