Advertisement

Journal of Computer-Aided Molecular Design

, Volume 16, Issue 2, pp 105–112 | Cite as

Can we separate active from inactive conformations?

  • David J. DillerEmail author
  • Kenneth M. MerzJr.
Article

Abstract

Molecular modeling methodologies such as molecular docking, pharmacophore modeling, and 3D-QSAR, rely on conformational searches of small molecules as a starting point. All of these methodologies seek conformations of the small molecules as they bind to target proteins, i.e., their active conformations. Thus the question as to whether active conformations can be separated from inactive conformations is extremely relevant. In this paper, 3D-descriptors that separate random conformations from active conformations of small molecules are sought. To select appropriate descriptors, 65 protein-ligand complexes were taken from the protein data bank. For each ligand the active conformation was compared to randomly generated low energy conformations. Descriptors such as solvent accessible surface area, number of internal interactions and radius of gyration appear to be useful for separating the active conformations from the random conformations. The results with all these descriptors indicate that active conformations are less compact that random conformations, i.e., they have more solvent accessible surface area, fewer internal interactions and a larger radius of gyration than random conformations. Thus these descriptors could be useful as weights to bias conformational search procedures to conformations more likely to bind to proteins or as filters to eliminate conformations unlikely to bind to any protein.

bound conformation conformational analysis surface area three-dimensional descriptors 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.Google Scholar
  2. 2.
    Kuntz, I.D., Science, 257 (1992) 1078.Google Scholar
  3. 3.
    Diller, D.J. and Merz, K.M., Proteins Struct. Funct. Genet., 43 (2001) 113.Google Scholar
  4. 4.
    Kearsley, S.K., Underwood, D.J., Sheridan, R.P. and Miller, M.D., J. Comput. Aid. Mol. Des., 8 (1994) 565.Google Scholar
  5. 5.
    Catalyst4.5., Molecular Simulations, I., San Diego, CA.Google Scholar
  6. 6.
    Greene, J., Kahn, S., Savoj, H., Sprague, P. and Teig, S., J. Chem. Inf. Comput. Sci., 34 (1994) 1297.Google Scholar
  7. 7.
    Cramer, R.D., III, Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.Google Scholar
  8. 8.
    Vieth, M., Hirst, J.D. and Brooks, C.L., III, J. Comput. Aid. Mol. Des., 12 (1998) 563.Google Scholar
  9. 9.
    Nicklaus, M.C., Wang, S., Driscoll, J.S. and Milne, G.W.A., Bioorg. Med. Chem., 3 (1995) 411.Google Scholar
  10. 10.
    Liljefors, T., Bostrom, J. and Norrby, P.-O., Conformational energies of protein-bound ligands. In Rational Molecular Design in Drug Research, Alfred Benzon Symp. 42, 1998, Munksgaard, Copenhagen.Google Scholar
  11. 11.
    Bostrom, J., Norrby, P.-O. and Liljefors, T., J. Comput. Aid. Mol. Des., 12 (1998) 383.Google Scholar
  12. 12.
    Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E., Nucleic Acids Res., 28 (2000) 235.Google Scholar
  13. 13.
    Berman, H.M., Bhat, T.N., Bourne, P.E., Feng, Z., Gilliland, G., Weissig, H. and Westbrook, J., Nat. Struct. Biol., 7 (2000) 957.Google Scholar
  14. 14.
    Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K. and Olson, A.J., J. Comp. Chem., 19 (1998) 1639.Google Scholar
  15. 15.
    Bohm, H.-J., J. Comput. Aid. Mol. Des., 8 (1994) 243.Google Scholar
  16. 16.
    Bohm, H.-J., J. Comput. Aid. Mol. Des., 12 (1998) 309.Google Scholar
  17. 17.
    Baxter, C.A., Murray, C.W., Clark, D.E., Westhead, D.R. and Eldridge, M.D., Proteins: Struct. Funct. Genet., 33 (1998) 367.Google Scholar
  18. 18.
    Jain, A.N., J. Comput. Aid. Mol. Des., 10 (1996) 427.Google Scholar
  19. 19.
    Bold, G., Altmann, K.-H., Frei, J., Lang, M., Manley, P.W., Traxler, P., Wietfeld, B., Brueggen, J., Buchdunger, E., Cozens, R., Ferrari, S., Furet, P., Hofmann, F., Martiny-Baron, G., Mestan, J., Roesel, J., Sills, M., Stover, D., Acemoglu, F., Boss, E., Emmenegger, R., Laesser, L., Masso, E., Roth, R., Schlachter, C., Vetterli, W., Wyss, D. and Wood, J.M., J. Med. Chem., 43 (2000) 2310.Google Scholar
  20. 20.
    Stewart, J.J., J Comput. Aid. Mol. Des., 4 (1990) 1.Google Scholar
  21. 21.
    Myers, M.R., Setzer, N.N., Spada, A.P., Persons, P.E., Ly, C.Q., Maguire, M.P., Zulli, A.L., Cheney, D.L., Zilberstein, A., Johnson, S.E., Franks, C.F. and Mitchell, K.J., Bioorg. Med. Chem. Lett., 7 (1997) 421.Google Scholar
  22. 22.
    Diller, D.J. and Verlinde, C.L.M.J., J. Comp. Chem., 20 (1999) 1740.Google Scholar
  23. 23.
    Lee, B. and Richards, F.M., J. Mol. Biol., 55 (1971) 379.Google Scholar
  24. 24.
    Rappe, A.K. and Goddard, W.A., III, J. Phys. Chem., 95 (1991) 3358.Google Scholar
  25. 25.
    Cerius2, Molecular Simulations, Inc, San Diego, CA.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  1. 1.Department of Molecular ModelingPharmacopeia, Inc., CN5350PrincetonUSA

Personalised recommendations