Journal of Computer-Aided Molecular Design

, Volume 15, Issue 12, pp 1137–1152 | Cite as

Reproducing the conformations of protein-bound ligands: A critical evaluation of several popular conformational searching tools

  • Jonas Boström


Several programs (Catalyst, Confort, Flo99, MacroModel, and Omega) that are commonly used to generate conformational ensembles have been tested for their ability to reproduce bioactive conformations. The ligands from thirty-two different ligand–protein complexes determined by high-resolution (le2.0 Å) X-ray crystallography have been analyzed. The Low-Mode Conformational Search method (with AMBER* and the GB/SA hydration model), as implemented in MacroModel, was found to perform better than the other algorithms. The rule-based method Omega, which is orders of magnitude faster than the other methods, also gave reasonable results but were found to be dependent on the input structure. The methods supporting diverse sampling (Catalyst, Confort) performed least well. For the seven ligands in the set having eight or more rotatable bonds, none of the bioactive conformations were ever found, save for one exception (Flo99). These ligands do not bind in a local minimum conformation according to AMBER*\GB/SA. Taking these last two observations together, it is clear that geometrically similar structures should be collected in order to increase the probability of finding the bioactive conformation among the generated ensembles. Factors influencing bioactive conformational retrieval have been identified and are discussed.

bioactive conformation Catalyst comparison conformational analysis Confort Flo99 high-resolution X-ray crystallography MacroModel Omega 


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  1. 1. a.
    Martin, Y.C., J. Med. Chem., 35 (1992) 2145. b. Martin, Y.C., Bures, M.G. and Willett, P., In Lipkowitz, K.B., Boyd, D.B. (eds), Reviews in Computational Chemistry, VCH Publishers, New York, 1990, pp. 213-263.Google Scholar
  2. 2.
    Marshall, G.R., Barry, C.D., Bosshard, H.E., Dammkoehler, R.A. and Dunn, D.A., in Olsen E.C., Christoffersen R.E. (eds), Computer-Assisted Drug Design., American Chemical Society Symposium: Washington DC, 1979, pp. 205-226.Google Scholar
  3. 3. a.
    Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 265 (1982) 269. b. Stoichet, B.K., Stroud, R.M., Santi, D.V., Kuntz, I.D. and Perry, K.M., Science, 259 (1993) 1445.Google Scholar
  4. 4. a.
    Vedani, A., McMasters, D.R. and Dobler, M., Quant. Struct.-Act. Relat., 19 (2000) 149. b. Guccione, S., Doweyko, A.M., Chen, H., Barretta, G.U. and Balzano, F., J. Comput. Aid. Mol. Des., 14 (2000) 647.Google Scholar
  5. 5.
    Allen, F.H., Davies, J.E., Galloy, J.J., Johnson, O., Kennard, O., Macrae, C.F., Mitchell, E.M., Mitchell, G.F., Smith, J.M., and Watson, D.G., J. Chem. Inf. Comput. Sci., 31 (1991) 187.Google Scholar
  6. 6.
    Corina, Molecular Networks, GmbH Computerchemie Langemarckplatz 1, Erlangen, Germany.Google Scholar
  7. 7.
    Sadowski, J., Gasteiger, J. and Klebe, G., J. Chem. Inf. Comput. Sci., 34 (1994) 1000.Google Scholar
  8. 8.
    MacroModel V7.0: Mohamadi, F., Richards, N.G.J., Guida, W.C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Hendrikson, T. and Still, W.C., J. Comput. Chem., 11 (1990) 440.Google Scholar
  9. 9.
    SYBYL molecular modeling software; TRIPOS Inc., 1699 South Hanley Road, Suite 303, St. Louis MO 63144.Google Scholar
  10. 10.
    Treasurywala, A.M., Jaeger, E.P. and Peterson, M.L., J. Comput. Chem., 17 (1996) 1171.Google Scholar
  11. 11.
    Leach, A., in Lipkowitz, K.B., Boyd, D.B. (eds), Reviews in Computational Chemistry, VCH Publishers, New York, 1991, pp. 1-47.Google Scholar
  12. 12.
    Bernstein, F., Koetzle, T.F., Williams, G.J.B., Meyer Jr, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Schimanouchi, T. and Tasumi, M.J., J. Mol. Biol., 112 (1977) 535.Google Scholar
  13. 13.
    Hendlich, M., Acta Crystallographica D54 (1998) 1178. Relibase is copyright Manfred Hendlich 1994-1999 and Cambridge Crystallographic Data Centre 1999, 2000.Google Scholar
  14. 14.
    The Omega program is available from OpenEye Science Software, 335c Winische Way, Santa Fe, NM 87501, U.S.A.Google Scholar
  15. 15. a.
    Spraque, P.W., Perspect. Drug Disc. Des. 3 (1995) 1. b. Spraque, P.W. and Hoffman, R., in Waterbeemd, H., Testa, B. and Folkers, G. (eds), Computer-Assisted Lead Finding and Optimization, VHCA, Basel, 1990, pp. 223-230.Google Scholar
  16. 16.
    Pearlman, R.S. and Balducci, R., Confort User's Manual, distributed by Tripos Inc., St. Louis, MO, U.S.A.Google Scholar
  17. 17. a.
    McMartin, C. and Bohacek, R. J. Comput. Aid. Mol. Des., 11 (1997) 333. b. McMartin, C. and Bohacek, R., J. Comput. Aid. Mol. Des., 9 (1995) 237.Google Scholar
  18. 18.
    Smellie, A., Teig, S.L., and Towbin, P., J. Comp. Chem., 16 (1995) 171.Google Scholar
  19. 19.
    Metropolis, N., Rosenbluth, A.W., Rosenbluth, M.N., Teller, A.H. and Teller, E., J. Chem. Phys., 21 (1953) 1087.Google Scholar
  20. 20. a.
    Kolossváry, I. and Guida, W.C., J. Am. Chem. Soc., 118 (1996) 5011. b. Kolossváry I. and Guida, W.C., J. Comput. Chem., 20 (1999) 1671.Google Scholar
  21. 21.
    Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., J. Am. Chem. Soc., 112 (1990) 6127.Google Scholar
  22. 22.
    Personal communication, Jens Sadowski, AstraZeneca R&D Mölndal, Sweden.Google Scholar
  23. 23.
    SPARTAN 5.1, Wavefunction, Inc.18401 Von Karman Ave., Ste. 370, Irvine, CA 92612 U.S.A.Google Scholar
  24. 24.
    Fox, T., Coll, J.T., Xie, X., Ford, P.J., Germann, U.A., Porter, M.D., Pazhanisamy, S., Fleming, M.A., Galullo, V., Su, M.S. and Wilson, K.P., Protein Sci., 7 (1998) 2249.Google Scholar
  25. 25.
    Boström, J., Norrby, P.-O. and Liljefors, T., J. Comput.-Aided. Mol. Des., 12 (1998) 383.Google Scholar
  26. 26.
    Kurinov, I.V. and Harrison, R.W., Nat. Struct. Biol., 1 (1994) 735.Google Scholar
  27. 27.
    Xu, Z., Bernlohr, D.A. and Banaszak, L.J., J. Biol. Chem., 268 (1993) 7874.Google Scholar
  28. 28.
    Pearlman, R.S., Concord User's Manual, distributed by Tripos Inc., St. Louis, MO, U.S.A.Google Scholar
  29. 29.
    Pastor, M., Cruciani., G., McLay, I., Pickett, S. and Clementi, S., J. Med. Chem., 43 (2000) 3233.Google Scholar
  30. 30. a.
    Howard, A.E., Singh, U.E., Billeter, M. and Kollman, P.A., J., Am. Chem. Soc., 110 (1988) 6984. b. Meng, E.C., Cieplak, P., Caldwell, J.W. and Kollman, P.A., J. Am. Chem. Soc., 116 (1994) 12061.Google Scholar

Copyright information

© Kluwer Academic Publishers 2001

Authors and Affiliations

  • Jonas Boström
    • 1
  1. 1.Department of Medicinal ChemistryAstraZeneca R&D MölndalSweden

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