Structural Chemistry

, Volume 7, Issue 2, pp 131–138 | Cite as

Calculations of the electrostatic free energy contributions to the binding free energy of sulfonamides to carbonic anhydrase

  • Jeffry D. Madura
  • Yasushi Nakajima
  • Rodney M. Hamilton
  • Andrzej Wierzbicki
  • Arieh Warshel


The interactions between biologically important enzymes and drugs are of great interest. In order to address some aspects of these interactions we have initiated a program to investigate enzymedrug interactions. Specifically, the interactions between one of the isozymes of carbonic anhydrase and a family of drugs known as sulfonamides have been studied using computational methods. In particular the electrostatic free energy of binding of carbonic anhydrase II with acetazolamide, methazolamide,p-chlorobenzenesulfonamide,p-aminobenzenesulfonamide and three new compounds (MK1, MK2, and MK3) has been computed using finite-difference Poisson-Boltzmann (FDPB) [1] method and the semimacroscopic version [2, 3] of the protein dipole Langevin dipole (PDLD) method [4]. Both methods, FDPB and PDLD, give similar results for the electrostatic free energy of binding even though different charges and different treatments were used for the protein. The calculated electrostatic binding free energies are in reasonable agreement with the experimental data. The potential and the limitation of electrostatic models for studies of binding energies are discussed.


Enzyme Sulfonamide Experimental Data Physical Chemistry Free Energy 
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  1. 1.
    Madura, J. D.; Davis, M. E.; Gilson, M. K.; Wade, R. C.; Luty, B. A.; McCammon, J. A. InRev. Comp. Chem. Boyd, D., Lipkowitz, K.; Ed.; VCH: New York, 1994; Vol. 5, p. 229.Google Scholar
  2. 2.
    Lee, F. S.; Chu, Z.-T.; Bolger, M. B.; Warshel, A.Protein Eng. 1992,5, 215.Google Scholar
  3. 3.
    Lee, F. S.; Chu, Z.-T.; Warshel, A.J. Comput. Chem. 1993,14, 161.Google Scholar
  4. 4.
    Warshel, A.Computer Modeling of Chemical Reactions in Enzymes and Solutions; Wiley: New York, 1991.Google Scholar
  5. 5.
    Kannan, K. K.; Petef, M.; Fridborg, K.; Cid-Dresdner, H., Lovgren, S.FEBS Lett. 1977,73, 115.Google Scholar
  6. 6.
    Taylor, P. W.; King, R. W.; Burgen, A. S. V.Biochem. 1970.Google Scholar
  7. 7.
    Eriksson, A. E.; Kylsten, P. M.; Jones, T. A.; Liljas, A.Proteins 1988,4, 283.Google Scholar
  8. 8.
    Merz, K. M.; Murcko, M. A.; Kollman, P. A.J. Am. Chem. Soc. 1991,113, 4484.Google Scholar
  9. 9.
    Vedani, A.; Meyer, J. E. F. InMolecular Dynamics and Protein Structure; Hermans, J., Ed.; Polycrystal Book Service: Western Springs, 1984.Google Scholar
  10. 10.
    Straatsma, T. P.; McCammon, J. A. InAnnu. Rev. Phys. Chem.; Strauss, H. L.; Babcock, G. T.; Leone, S. R.; Ed.; Annual Reviews, Inc.: Palo Alto, 1992; Vol. 43, p 407.Google Scholar
  11. 11.
    Warshel, A.; Aqvist, J. InAnn. Rev. Biophys. Biophys. Chem. Annual Reviews, Inc.: 1991; Vol. 20; p 267.Google Scholar
  12. 12.
    Aqvist, J.; Medina, C.; Samuelsson, J.-E.Protein Eng. 1994,7, 385.Google Scholar
  13. 13.
    Warshel, A.; Tao, H.; Fothergill, M.; Chu, Z.-T.Isr. J. Chem. 1994,54, 253.Google Scholar
  14. 14. (a)
    Davis, M. E.; McCammon, J. A.Chem. Rev. 1990,90, 509.Google Scholar
  15. 14. (b)
    Nicholls, A.; Honig, B.J. Comput. Chem. 1991,12, 435.Google Scholar
  16. 15.
    King, G.; Lee, F. S.; Warshel, A.J. Chem. Phys. 1991,95, 4366.Google Scholar
  17. 16.
    Chirlian, L. E.; Francl, M. M.J. Comput. Chem. 1987,8, 894.Google Scholar
  18. 17.
    Quanta 4.0 molecular modeling software from Molecular Simulations, Inc. Burlington, MA, 1994.Google Scholar
  19. 18.
    Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, J. E. F.; Brice, M. D.; Rogers, J. R.; Kennard, O.; Shimanouchi, T.; Tasumi, J.Mol. Biol. 1977,112, 535.Google Scholar
  20. 19. (a)
    Gilson, M. K., Sharp, K. A., Honig, B. H.J. Comput. Chem. 1987,9, 327.Google Scholar
  21. 19. (b)
    Madura, J. D.; Briggs, J. M.; Wade, R. C., Davis, M. E.; Luty, B. A.; Ilin, A.; Antosciewicz, J.; Gilson, M. K.; Bagheri, B.; Scott, L. R.; McCammon, J. A.Comput. Phys. Commun. 1995,91, 57.Google Scholar
  22. 20.
    Maren, T. H.Mol. Pharm. 1991,41, 419.Google Scholar
  23. 21.
    American Chemical Society Presidential Satellite Television Seminar: Molecular Modeling in the Discovery of New Drugs: American Chemical Society: Washington, DC, 1993.Google Scholar
  24. 22.
    Parson, W. W.; Chu, Z.-T.; Warshel, A.Biochim. Biophys. Acta 1990,1017, 251.Google Scholar
  25. 23.
    Aqvist, J.; Leucke, H.; Quiocho, F. A.; Warshel, A.Proc. Natl. Acad. Sci., USA 1991,88, 2026.Google Scholar
  26. 24.
    Mohan, V.; Davis, M. E.; McCammon, J. A.; Pettitt, B. M.J. Phys. Chem. 1992,96, 6428.Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Jeffry D. Madura
    • 1
  • Yasushi Nakajima
    • 1
  • Rodney M. Hamilton
    • 1
  • Andrzej Wierzbicki
    • 1
  • Arieh Warshel
    • 2
  1. 1.Department of ChemistryUniversity of South AlabamaMobile
  2. 2.Department of ChemistryUniversity of Southern CaliforniaLos Angeles

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