Journal of Computer-Aided Molecular Design

, Volume 16, Issue 10, pp 741–753 | Cite as

The consequences of translational and rotational entropy lost by small molecules on binding to proteins

  • Christopher W. Murray
  • Marcel L. Verdonk


When a small molecule binds to a protein, it loses a significant amount of rigid body translational and rotational entropy. Estimates of the associated energy barrier vary widely in the literature yet accurate estimates are important in the interpretation of results from fragment-based drug discovery techniques. This paper describes an analysis that allows the estimation of the rigid body entropy barrier from the increase in binding affinities that results when two fragments of known affinity and known binding mode are joined together. The paper reviews the relatively rare number of examples where good quality data is available. From the analysis of this data, we estimate that the barrier to binding, due to the loss of rigid-body entropy, is 15–20 kJ/mol, i.e. around 3 orders of magnitude in affinity at 298 K. This large barrier explains why it is comparatively rare to observe multiple fragments binding to non-overlapping adjacent sites in enzymes. The barrier is also consistent with medicinal chemistry experience where small changes in the critical binding regions of ligands are often poorly tolerated by enzymes.

rigid-body entropy fragment binding structure-based design empirical scoring functions. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hird, N., Drug Disc. Today, 5 (2000) 307.Google Scholar
  2. 2.
    Teague, S.J., Davis, A.M., Leeson, P.D. and Oprea, T., Angew. Chem. Int. Ed., 38 (1999) 3743.Google Scholar
  3. 3.
    Hann, M.M., Leach, A.R. and Harper, G., J. Chem. Inf. Comput. Sci. 41 (2001) 856.Google Scholar
  4. 4.
    Shuker, S.B., Hajduk, P.J., Meadows, R.P. and Fesik, S.W. Science, 274 (1996) 1531.Google Scholar
  5. 5.
    Fejzo, J., Lepre, C.A., Peng., J.W., Bemis, G.W., Ajay, Murcko, M.A. and Moore, J.M., Chem. Biol., 6 (1999) 755.Google Scholar
  6. 6.
    Boehm, H.-J., Boehringer, M., Bur, D., Gmuender, H., Huber, W., Klaus, W., Kostrewa, D., Kuehne, H., Luebbers, T., Meunier-Keller, N. and Mueller, F., J. Med. Chem., 43 (2000) 2664.Google Scholar
  7. 7.
    Nienaber, V.L., Richardson, P.L., Klighofer, V., Bouska, J.J., Giranda, V.L. and Greer, J., Nature Biotech., 18 (2000) 1105.Google Scholar
  8. 8.
    Maly, D.C., Choong, I.C. and Ellman, J.A. Proc. Natl. Acad. Sci. USA, 97 (2000) 2419.Google Scholar
  9. 9.
    Erlanson, D.A., Braisted, A.C., Raphael, D.R., Randal, M., Stroud, R.M., Gordon, E.M. and Wells, J.A., Proc. Natl. Acad. Sci. USA, 97 (2000) 9367.Google Scholar
  10. 10.
    Blundell, T.L., Jhoti, H. and Abell, C., Nature Rev., 11 (2002) 45.Google Scholar
  11. 11.
    Page, M.I. and Jencks, W.P. Proc. Natl. Acad. Sci. USA, 68 (1971) 1678.Google Scholar
  12. 12.
    Page, M.I. Chem. Soc. Rev 1973, 295Google Scholar
  13. 13.
    Jencks, W.P. Proc. Natl. Acad. Sci. USA, 78 (1981) 4046.Google Scholar
  14. 14.
    Hajduk, P.J., Boyd, S., Nettesheim, D., Nienaber, V., Severin, J., Smith, R., Davidson, D., Rockway, T. and Fesik, S.W., J. Med. Chem., 43 (2000) 3862.Google Scholar
  15. 15.
    Hajduk, P.J., et al., J. Med. Chem., 40 (2000) 3144.Google Scholar
  16. 16.
    Hajduk, P.J., Zhou, M.-M. and Fesik, S.W., Bioorg. Med. Chem. Lett., 16 (2000) 2403.Google Scholar
  17. 17.
    Hajduk, P.J., Dinges, J., Schkeryantz, J.M., Janowick, D., Kaminski, M., Tufano, M., Augeri, D.J., Petros, A., Nienaber, V., Zhong, P., Hammond, R., Coen, M., Beutel, B., Katz, L. and Fesik, S.W., J. Med. Chem., 42 (1999) 3852.Google Scholar
  18. 18.
    Hajduk, P.J., Sheppard, G., Nettesheim, D.G., Olejniczak, E.T., Shuker, S.B., Meadows, R.P., Steinman, D.H., Carrera, G.M., Marcotte, P.A., Severin, J., Walter, K., Smith, H., Gubbins, E., Simmer, R., Holzman, T.F., Morgan, D.W., Davidsen, S.K. and Fesik, S.W. J. Am. Chem. Soc., 119 (1997) 5818.Google Scholar
  19. 19.
    Green, N.M., Adv. Protein Chem. 29 (1975) 85.Google Scholar
  20. 20.
    Schaschke, N., Matschiner, G., Zettl, F., Marquardt, U., Bergner, A., Bode, W., Sommerhoff, C.P. and Moroder, L. Chem. Biol., 8 (2001) 313.Google Scholar
  21. 21.
    Rao, J. and Whitesides, G.M., J. Am. Chem. Soc. 119 (1997) 10286.Google Scholar
  22. 22.
    Rao, J., Lahiri, J., Isaacs, L., Weis, R.M. and Whitesides, G.M., Science 280 (1998) 708.Google Scholar
  23. 23.
    Pugliese, L., Coda, A., Malcovati, M. and Bolnesi, M., J. Mol. Biol., 231 (1993) 698.Google Scholar
  24. 24.
    Puius, Y.A., et al., Proc., Natl., Acad. Sci. USA, 94 (1997) 13420.Google Scholar
  25. 25.
    Stout, T.J., Sage, C.R. and Stroud R.M., Structure, 6 (1998) 839.Google Scholar
  26. 26.
    Mao, C. et al., Biochemistry, 37 (1998) 7135.Google Scholar
  27. 27.
    Rice, K.D., Gangloff, A.R., Kuo, E.Y.-L., Dener, J.M., Wang, V.R., Lum, R., Newcomb, W.S., Havel, C., Putnam, D., Cregar, L., Wong, M. and Warne, R.L., Bioorg. Med. Chem. Lett., 10 (2000) 2357.Google Scholar
  28. 28.
    Mammen, M., Choi, S.-K. and Whitesides, G.W. Angew. Chem. Int. Ed., 37 (1998) 2754.Google Scholar
  29. 29.
    Rao, J., Lahiri, J., Weis, R.M., Whitesides, G.M., J. Am. Chem. Soc. 122 (2000) 2698.Google Scholar
  30. 30.
    McQuarrie, D.A. Statistical Mechanics, D.A., Harper and Row, New York, 1976.Google Scholar
  31. 31.
    Finkelstein, A.V. and Janin, J., Protein Engineering 3 (19898), 1–3.Google Scholar
  32. 32.
    Wertz, D.H., J. Am. Chem. Soc. 102 (1980) 5316.Google Scholar
  33. 33.
    Mammen, M., Shakhnovich, E.I., Deutch, J.M. and Whitesides G.M., J. Org. Chem. 63 (1998) 3821.Google Scholar
  34. 34.
    Murphy, K.P., Xie, D., Thompson, K.S., Amzel, M. and Freire, E., Proteins: Struc. Func. Gen. 18 (1994) 63.Google Scholar
  35. 35.
    Sadowski, J. and Gasteiger, J., Chem. Rev. 93 (1993) 2567.Google Scholar
  36. 36.
    Page, M.I. Angew Chemie Int. Ed. 16 (1977) 449.Google Scholar
  37. 37.
    Kirby, A.J., Adv. Phys. Org. Chem. 1980, 17, 225.Google Scholar
  38. 38.
    Searle, M.S. and Williams, D.H., J. Am. Chem. Soc. 114 (1992) 10690.Google Scholar
  39. 39.
    Gilson, M.K., Given, J.A., Bush, B.L., McCammon, A., Biophysical Journal 72 (1997), 1047–1069.Google Scholar
  40. 40.
    Böhm, H.-J., J. Comput.-Aided Mol. Design, 8 (1994) 243.Google Scholar
  41. 41.
    Böhm, H.-J., J. Comput.-Aided Mol. Design 12 (1998) 309.Google Scholar
  42. 42.
    Jain, A.J., J. Comput.-Aided Mol. Design 10 (1996) 10, 427.Google Scholar
  43. 43.
    Head, R.D., Smythe, M.L., Oprea, T.I., Waller, C.L., Green, S.M. and Marshall, G.R., J. Am. Chem. Soc., 118 (1996) 3959.Google Scholar
  44. 44.
    Andrews, P.R., Craik, D.J. and Martin, J.L., J. Med. Chem. 27 (1984) 1648.Google Scholar
  45. 45.
    Mammen, M., Shakhnovich, E.I. and Whitesides G.M., J. Org. Chem. 63 (1998) 3168.Google Scholar
  46. 46.
    Rejto, P.A. and Verkhiver, G.M., Proc. Natl. Acad. Sci. 93 (1996) 8945.Google Scholar
  47. 47.
    Kuntz, I.D., Chen, K., Sharp, K.A. and Kollman, P.A., Proc. Natl. Acad. Sci. 96 (1999) 9997.Google Scholar
  48. 48.
    Eldridge, M.D., Murray, C.W., Auton, T.R., Paolini, G.V. and Mee, R.P., J. Comput.-Aided Mol. Design, 11 (1997) 425.Google Scholar
  49. 49.
    Wang, R., Liu, L., Lai, L. and Tang, Y., J. Mol. Model. 4 (1998) 379.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Christopher W. Murray
    • 1
  • Marcel L. Verdonk
    • 1
  1. 1.Astex Technology LtdMilton Road, CambridgeUK

Personalised recommendations