Abstract
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.
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References
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.
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.
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.
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.
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.
Corina, Molecular Networks, GmbH Computerchemie Langemarckplatz 1, Erlangen, Germany.
Sadowski, J., Gasteiger, J. and Klebe, G., J. Chem. Inf. Comput. Sci., 34 (1994) 1000.
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.
SYBYL molecular modeling software; TRIPOS Inc., 1699 South Hanley Road, Suite 303, St. Louis MO 63144.
Treasurywala, A.M., Jaeger, E.P. and Peterson, M.L., J. Comput. Chem., 17 (1996) 1171.
Leach, A., in Lipkowitz, K.B., Boyd, D.B. (eds), Reviews in Computational Chemistry, VCH Publishers, New York, 1991, pp. 1-47.
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.
Hendlich, M., Acta Crystallographica D54 (1998) 1178. Relibase is copyright Manfred Hendlich 1994-1999 and Cambridge Crystallographic Data Centre 1999, 2000.
The Omega program is available from OpenEye Science Software, 335c Winische Way, Santa Fe, NM 87501, U.S.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.
Pearlman, R.S. and Balducci, R., Confort User's Manual, distributed by Tripos Inc., St. Louis, MO, U.S.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.
Smellie, A., Teig, S.L., and Towbin, P., J. Comp. Chem., 16 (1995) 171.
Metropolis, N., Rosenbluth, A.W., Rosenbluth, M.N., Teller, A.H. and Teller, E., J. Chem. Phys., 21 (1953) 1087.
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.
Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., J. Am. Chem. Soc., 112 (1990) 6127.
Personal communication, Jens Sadowski, AstraZeneca R&D Mölndal, Sweden.
SPARTAN 5.1, Wavefunction, Inc.18401 Von Karman Ave., Ste. 370, Irvine, CA 92612 U.S.A.
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.
Boström, J., Norrby, P.-O. and Liljefors, T., J. Comput.-Aided. Mol. Des., 12 (1998) 383.
Kurinov, I.V. and Harrison, R.W., Nat. Struct. Biol., 1 (1994) 735.
Xu, Z., Bernlohr, D.A. and Banaszak, L.J., J. Biol. Chem., 268 (1993) 7874.
Pearlman, R.S., Concord User's Manual, distributed by Tripos Inc., St. Louis, MO, U.S.A.
Pastor, M., Cruciani., G., McLay, I., Pickett, S. and Clementi, S., J. Med. Chem., 43 (2000) 3233.
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.
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Boström, J. Reproducing the conformations of protein-bound ligands: A critical evaluation of several popular conformational searching tools. J Comput Aided Mol Des 15, 1137–1152 (2001). https://doi.org/10.1023/A:1015930826903
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DOI: https://doi.org/10.1023/A:1015930826903