Journal of Computer-Aided Molecular Design

, Volume 15, Issue 10, pp 935–960 | Cite as

Functional group placement in protein binding sites: a comparison of GRID and MCSS

  • Ryan Bitetti-Putzer
  • Diane Joseph-McCarthy
  • James M. Hogle
  • Martin Karplus


One approach to combinatorial ligand design begins by determining optimal locations (i.e., local potential energy minima) for functional groups in the binding site of a target macromolecule. MCSS and GRID are two methods, based on significantly different algorithms, which are used for this purpose. A comparison of the two methods for the same functional groups is reported. Calculations were performed for nonpolar and polar functional groups in the internal hydrophobic pocket of the poliovirus capsid protein, and on the binding surface of the src SH3 domain. The two approaches are shown to agree qualitatively; i.e., the global characteristics of the functional group maps generated by MCSS and GRID are similar. However, there are significant differences in the relative interaction energies of the two sets of minima, a consequence of the different functional form used to evaluate polar interactions (electrostatics and hydrogen bonding) in the two methods. The single sphere representation used by GRID affords only positional information, supplemented by the identification of hydrogen bonding interactions. By contrast, the multi-atom representation of most MCSS groups yields in both positional and orientational information. The two methods are most similar for small functional groups, while for larger functional groups MCSS yields results consistent with GRID but superior in detail. These results are in accord with the somewhat different purposes for which the two methods were developed. GRID has been used mainly to introduce functionalities at specific positions in lead compounds, in which case the orientation is predetermined by the structure of the latter. The orientational information provided by MCSS is important for its use in the de novo design of large, multi-functional ligands, as well as for improving lead compounds.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Goodford, P.J., J. Med. Chem., 28 (1985) 849.Google Scholar
  2. 2.
    Boobbyer, D.N.A., Goodford, P.J., McWhinnie, P.M. and Wade, R.C., J. Med. Chem., 32 (1989) 1083.Google Scholar
  3. 3.
    Wade, R.C., Clark, K.J. and Goodford, P.J., J. Med. Chem., 36 (1993) 140.Google Scholar
  4. 4.
    Wade, R.C. and Goodford, P.J., J.Med. Chem., 36 (1993) 148.Google Scholar
  5. 5.
    Evensen, E., Joseph-McCarthy, D. and Karplus, M., MCSSv2, Harvard University, 1997.Google Scholar
  6. 6.
    Miranker, A. and Karplus, M., Proteins, 11 (1991) 29.Google Scholar
  7. 7.
    Caflisch, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.Google Scholar
  8. 8.
    Caflisch, A. and Karplus, M., Perspectives in Drug Discovery and Design, 3 (1995) 51.Google Scholar
  9. 9.
    Jedrzejas, M.J., Singh, S., Brouillette, W.J., Air, G.M. and Luo, M., Proteins, 23 (1995) 264.Google Scholar
  10. 10.
    von Itzstein, M., Dyason, J., Oliver, S., White, H., Wu, W., Kok, G. and Pegg, M., J. Med. Chem., 39 (1996) 388.Google Scholar
  11. 11.
    Appelt, K., Bacquet, R.J., Bartlett, C.A., Booth, C.L.J., Freer, S.T., Fuhry, M.A.M., Gehring, M.R., Herrmann, S.M., Howland, E.F., Jansen, C.A., Reddy, M.R., Reich, S.H., Schoettlin, W.S., Smith, W.W., Varney, M.D., Villafranca, J.E., Ward, R.W., Webber, S., Webber, S.E., Welsh, K.M. and White, J., J. Med. Chem., 34 (1991) 1925.Google Scholar
  12. 12.
    Goodford, P.J., GRID User Manual, Edition 16.Google Scholar
  13. 13.
    Joseph-McCarthy, D., Hogle, J.M. and Karplus, M., Proteins, 29 (1997) 32.Google Scholar
  14. 14.
    Hogle, J.M., Chow, M. and Filman, D.J., Science, 229 (1985) 1358.Google Scholar
  15. 15.
    Filman, D.J., Syed, R., Chow, M., Macadam, A.J., Minor, P.D. and Hogle, J.M., EMBO J., 8 (1989) 1567.Google Scholar
  16. 16.
    Grant, R.A., Hiremath, C.N., Filman, D.J., Syed, R., Andries, K. and Hogle, J.M., Curr. Biol., 4 (1994) 784.Google Scholar
  17. 17.
    Hiremath, C., Grant, R.A., Filman, D.J. and Hogle, J.M., Acta Cryst., D51 (1995) 473.Google Scholar
  18. 18.
    Hiremath, C.N., Filman, D.J., Grant, R.A. and Hogle, J.M., Acta Cryst., D53 (1997) 558.Google Scholar
  19. 19.
    Rossmann, M.G., Arnold, E., Erickson, J.W., Frankenberger, E.A., Griffith, J.P., Hecht, H.-J., Johnson, Kamer, G., Luo, M., Mosser, A.G., Rueckert, R.R., Sherry, B. and Vriend, G., Nature, 317 (1985) 145.Google Scholar
  20. 20.
    Kim, K.H., Willingmann, P., Gong, Z.X., Kremer, M.J., Chapman, M.S., Minor, I., Oliveira, M.A., Rossmann, M.G., Andries, K., Diana, G.D., Dutko, F.J., McKinlay, M.A. and Pevear, D.C., J. Mol. Biol., 230 (1993) 206.Google Scholar
  21. 21.
    Badger, J.; Minor, I., Kremer, M.J., Oliveira, M.A., Smith, T.J., Griffith, J.P., Guerin, D.M.A., Krishnaswamy, S., Luo, M., Rossmann, M.G., McKinlay, M.A., Diana, G.D., Dutko, F.J., Fancher, M., Rueckert, R.R. and Heinz, B.A., Proc. Natl. Acad. Sci. USA, 85 (1988) 3304.Google Scholar
  22. 22.
    Badger, J., Minor, I., Oliveira, M.A., Smith, T.J. and Rossmann, M.G., Proteins, 6 (1989) 1.Google Scholar
  23. 23.
    Feng, S., Kapoor, T.M., Shirai, F., Combs, A.P. and Schreiber, S.L., Chem. Biol., 3 (1996) 661.Google Scholar
  24. 24.
    MacKerell, A.D., Bashford, D., Bellot, M., Dunbrack, R.L., Evanseck, J.D., Field, M.J., Fischer, S., Gao, J., Guo, H., Ha, S., Joseph-McCarthy, D., Kuchnir, L., Kuczera, K., Lau, F.T.K., Mattos, C., Michnick, S., Ngo, T., Nguyen, D.T., Prodhom, B., Reiher, W.E., Roux, B., Schlenkrich, M., Smith, J.C., Stote, R., Straub, J., Watanabe, M., Wiorkiewicz-Kuczera, J., Yin, D. and Karplus, M., J. Phys. Chem. B, 102 (1998) 3586.Google Scholar
  25. 25.
    Brünger, A.T., Kuriyan, J. and Karplus, M., Science, 235 (1987) 458.Google Scholar
  26. 26.
    Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., J. Comp. Chem., 4 (1983) 187.Google Scholar
  27. 27.
    Elber, R. and Karplus, M., J. Am. Chem. Soc., 112 (1990) 9161.Google Scholar
  28. 28.
    Neria, E., Fischer, S. and Karplus, M., J. Chem. Phys., 105 (1996) 1902.Google Scholar
  29. 29.
    Halgren, T.A., J. Comput. Chem., 17 (1996) 490.Google Scholar
  30. 30.
    Eisen, M.B., Wiley, D.C., Karplus, M. and Hubbard, R.E., Proteins, 19 (1994) 199.Google Scholar
  31. 31.
    Miranker, A. and Karplus, M., Proteins, 23 (1995) 472.Google Scholar
  32. 32.
    Tsang, S.K., Cheh, J., Isaacs, L., Joseph-McCarthy, D., Choi, S.K., Pevear, D.C., Whitesides, G.M. and Hogle, J.M., Chem. Biol., 8 (2001) 33.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Ryan Bitetti-Putzer
    • 1
    • 2
    • 3
  • Diane Joseph-McCarthy
    • 3
    • 4
  • James M. Hogle
    • 1
    • 3
  • Martin Karplus
    • 1
    • 3
    • 5
  1. 1.Committee on Higher Degrees in BiophysicsHarvard UniversityCambridgeUSA
  2. 2.Department of Chemistry and Chemical BiologyHarvard UniversityCambridgeUSA
  3. 3.Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBostonUSA
  4. 4.Biological Chemistry DepartmentWyeth ResearchCambridgeUSA
  5. 5.Laboratoire de Chimie Biophysique, ISISUniversité Louis PasteurStrasbourgFrance

Personalised recommendations