Journal of Computer-Aided Molecular Design

, Volume 12, Issue 6, pp 563–572 | Cite as

Do active site conformations of small ligands correspond to low free-energy solution structures?

  • Michal Vieth
  • Jonathan D. Hirst
  • Charles L. BrooksIII

Abstract

We compare the low free energy structures of ten small, polar ligands in solution to their conformations in their respective receptor active sites. The solution conformations are generated by a systematic search and the free energies of representative structures are computed with a continuum solvation model. Based on the values of torsion angles, we find little similarity between low energy solution structures of small ligands and their active site conformations. However, in nine out of ten cases, the positions of 'anchor points' (key atoms responsible for tight binding) in the lowest energy solution structures are very similar to the positions of these atoms in the active site conformations. A metric that more closely captures the essentials of binding supports the basic premise underlying pharmacophore mapping, namely that active site conformations of small flexible ligands correspond to their low energy structures in solution. This work supports the efforts of building pharmacophore models based on the information present in solution structures of small isolated ligands.

anchor points conformational search ligand binding 

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References

  1. 1.
    Clark, D.E., Westhead, D.R., Sykes, R.A. and Murray, C.W., J. Comput.-Aided Mol. Design, 10 (1996) 397.Google Scholar
  2. 2.
    Martin, Y.C., J. Med. Chem., 35 (1992) 2145.Google Scholar
  3. 3.
    Wang, S., Zaharewitz, D.W., Sharma, R., Marquez, V.E., Lewin, N.E., Du, L., Blumberg, P.M. and Milne, G.W., J. Med. Chem., 37 (1994) 4479.Google Scholar
  4. 4.
    Kiyama, R., Honma, T., Hayashi, K., Ogawa, M., Hara, M., Fujimoto, M. and Fujishita, T.J., J. Med. Chem., 38 (1995) 2728.Google Scholar
  5. 5.
    Klebe, G., J. Mol. Biol., 237 (1994) 212.Google Scholar
  6. 6.
    Hodgkin, E.E., Miller, A. and Whittaker, M., J. Comput.-Aided Mol. Design, 7 (1993) 515.Google Scholar
  7. 7.
    Dammkoehler, R.A., Karasek, S.F., Shands, E.F. and Marshall, G.R., J. Comput.-Aided. Mol. Design, 3 (1989) 3.Google Scholar
  8. 8.
    Dammkoehler, R.A., Karasek, S.F., Shands, E.F. and Marshall, G.R., J. Comput.-Aided Mol. Design, 9 (1995) 491.Google Scholar
  9. 9.
    Jones, G., Willet, P. and Glen, R.C., J. Comput.-Aided Mol. Design, 9 (1995) 532.Google Scholar
  10. 10.
    Mayer, D., Naylor, C.B., Motoc, I. and Marshall, G.R., J. Comput.-Aided Mol. Design, 1 (1987) 3.Google Scholar
  11. 11.
    Sheridan, R.P., Nilakantan, R., Dixon, J.S. and Venkataraghavan, R., J. Med. Chem., 29 (1986) 899.Google Scholar
  12. 12.
    Schwyzer, R., Biopolymers, 37 (1995) 5.Google Scholar
  13. 13.
    Fisher, E. and Thierfelder, H., Berl. Dtsh, Chem. Ges., 27 (1894) 2985.Google Scholar
  14. 14.
    Jorgensen, W.L., Science, 254 (1991) 954.Google Scholar
  15. 15.
    Patten, P.A., Gray, N.S., Yang, P.L., Marks, C.B., Wedemayer, G.J., Boniface, J.J., Stevens, R.C. and Schultz, P.G., Science, 271 (1996) 1086.Google Scholar
  16. 16.
    Böhm, H.-J. and Klebe, G., Angew. Chem. Int. Ed. Engl., 35 (1996) 2588.Google Scholar
  17. 17.
    Nicklaus, M.C., Shaomeng, W., Driscoll, J.S. and Milne, W.A., Bioorg. Med. Chem., 3 (1995) 411.Google Scholar
  18. 18.
    Klebe, G. In Burgi, H.B. and Dunitz, J.D. (Eds.) Structure Correlation, VCH, Weinheim, 1994, p. 543.Google Scholar
  19. 19.
    Allen, F.H. In Domenicano, A. and Hargittai, I. (Eds.) Accurate Molecular Structures, Oxford University Press, Oxford, 1992, p. 355.Google Scholar
  20. 20.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.Google Scholar
  21. 21.
    Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., J. Comput. Chem., 4 (1983) 187.Google Scholar
  22. 22.
    Quanta, Molecular Simulations Inc., San Diego, CA, 1997.Google Scholar
  23. 23.
    Gaussian 94, Gaussian, Inc., Pittsburgh, PA, 1995.Google Scholar
  24. 24.
    Vieth, M., Parameter files for ligands are available through anonymous ftp from ftp.scripps.edu/ficio/parameters/ or from our web site at www.scripps.edu/brooks/ficio/parameters/param.html, 1997.Google Scholar
  25. 25.
    Miranker, A. and Karplus, M., Proteins, 11 (1991) 29.Google Scholar
  26. 26.
    Cerius2, Molecular Simulations Inc., San Diego, CA, 1997.Google Scholar
  27. 27.
    Catalyst, Molecular Simulations Inc., San Diego, CA, 1997.Google Scholar
  28. 28.
    Jain, A.K. and Dubes, R.C., Algorithms for clustering data, Prentice Hall, Englewood Cliffs, NJ, 1988.Google Scholar
  29. 29.
    Warwicker, J. and Watson, H.C., J. Mol. Biol., 157 (1982) 671.Google Scholar
  30. 30.
    Edinger, S.R., Cortis, C., Shenkin, P.S. and Friesner, R.A., J. Phys. Chem., B101 (1997) 1190.Google Scholar
  31. 31.
    Allen, F.H., Bellard, S., Brice, M.D., Cartwright, B.A., Doubleday, A., Higgs, A., Hummelink-Peters, T., Kennard, O., Motherwell, W.D.S., Rodgers, J.R. and Watson, D.G., Acta Crystallogr., 35 (1979) 2331.Google Scholar
  32. 32.
    Weber, P.C., Ohlendorf, D.H., Wendoloski, J.J. and Salemme, F.R., Science, 243 (1989) 85.Google Scholar
  33. 33.
    Segal, D.M., Padlan, E.A., Cohen, G.H., Rudikoff, S., Potter, M. and Davies, D.R., Proc. Natl. Acad. Sci. USA, 71 (1974) 4298.Google Scholar
  34. 34.
    Weis, W.I., Brünger, A.T., Skehel, J.J. and Wiley, D.C., J. Mol. Biol., 212 (1990) 737.Google Scholar
  35. 35.
    Robbins, A.H. and Stout, C.D., Proc. Natl. Acad. Sci. USA, 86 (1989) 3639.Google Scholar
  36. 36.
    Noble, M.E.M., Wierenga, R.K., Lambeir, A.M., Opperdoes, F.R., Thunnissen, A.M.W.H., Kalk, K.H., Groendijk, H. and Hol, W.G.J., Proteins, 10 (1991) 50.Google Scholar
  37. 37.
    Walter, J., Steigemann, W., Singh, T.P., Bartunik, H., Bode, W. and Huber, R., Acta Crystallogr. B, 38 (1982) 1462.Google Scholar
  38. 38.
    Christianson, D.W. and Lipscomb, W.N., Proc. Natl. Acad. Sci. USA, 83 (1986) 7568.Google Scholar
  39. 39.
    Holden, H.M. and Matthews, B.W., J. Biol. Chem., 263 (1988) 3256.Google Scholar
  40. 40.
    Leslie, A.G.W., J. Mol. Biol., 213 (1990) 167.Google Scholar
  41. 41.
    Tronrud, D.E., Monzingo, A.F. and Matthews, B.W., Eur. J. Biochem., 157 (1986) 261.Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Michal Vieth
    • 1
  • Jonathan D. Hirst
    • 1
  • Charles L. BrooksIII
    • 1
  1. 1.Department of Molecular BiologyThe Scripps Research InstituteLa JollaU.S.A. Current address: Department of Computational Chemistry and Macromolecular Structure Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46032, U.S.A

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