Abstract
In this article we present an implementation of a de novo drug-design algorithm. The algorithm starts with a molecule placed in the binding site of a protein and then modifies it using a sequential growth approach. This involves successive cycles of suppression of randomly picked groups in the molecule and their replacement by other groups chosen from databanks of linear or cyclic fragments. The algorithm has been coupled with the Dynamo library which allows the simulation of macromolecules using molecular mechanical and quantum chemical methods. The main body of the article describes the methodologies we use to create, characterize and evaluate putative ligands. We also consider briefly an application of the algorithm to a protein of pharmacological interest, the neuraminidase of the influenza virus, and discuss the strengths and weaknesses of our approach.
Similar content being viewed by others
References
Whittle, P.J. and Blundell, T.L. Annu. Rev. Biophys. Biomol. Struct., 23 (1994) 349.
Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.
Rarey, M., Kramer, B., Lengauer, T. and Klebe, G., J. Mol. Biol., 261 (1996) 470.
Jones, G., Willett, P., Glen, R.C., Leach, A.R. and Taylor, R., J. Mol. Biol., 267 (1997) 727.
Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K. and Olson, A.J., J. Comput. Chem., 19 (1990) 1639.
Böhm, H.J., J. Comput.-Aided. Mol. Des., 6 (1992) 593.
Westhead, D.R., Clark, D.E., Frenkel, D., Li, J., Murray, C.W., Robson, B. and Waszkowycz, B., J. Comput.-Aided Mol. Des., 9 (1995) 139.
Moon, J.B. and Howe, W.J., Proteins, 11 (1991) 314.
Gillet, V., Newell, W., Mata, P., Myatt, G., Sike, S., Zsoldos, Z. and Johnson, A.P., J. Chem. Inf. Comput. Sci., 34 (1994) 207.
Field, M.J., A Practical Introduction to the Simulation of Molecular Systems. Cambridge University Press, Cambridge, UK, 1999.
Field, M.J., Albe, M., Bret, C., Proust-De Martin, F. and Thomas, A., J. Comput. Chem., 21 (2000) 1088.
Laver, W.G., Bischofberger, N. and Webster, R.G., Sci. Am., 280 (1999) 78.
Pellegrini, E., Elaboration d'un Algorithme de Drug Design: Aspects Fondamentaux et Application à une Protéine., Ph.D Thesis, Université Joseph Fourier, Grenoble, France, 2002.
Berman, H.M., Battistuz, T., Bhat, T.N., Bluhm, W.F., Bourne, P.E., Burkhardt, K., Feng, Z., Gilliland, G.L., Iype, L., Jain, S., Fagan, P., Marvin, J., Padilla, D., Ravichandran, V., Schneider, B., Thanki, N., Weissig, H., Westbrook, J.D. and Zardecki, C., Acta Crystallogr. D. Biol. Crystallogr., 58 (2002) 899.
Lewell X.-Q., Judd D.B., Watson S.P., and Hann M.M., J. Chem. Inf. Comput. Sci., 38 (1998) 511.
Schneider G., Lee M.-L., Stahl M., and Schneider, P., J. Comput.-Aided Mol. Des., 14 (2000) 487.
Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J., Adv. Drug Deliv. Rev., 118 (1997) 3.
Gasteiger, J., Rudolph, C. and Sadowski, J., Tetrahedron Comp. Method., 3 (1990) 537.
Rappé, A.K., Casewit, C.J., Colwell, K.S., Goddard III, W.A. and Skiff, W.M., J. Am. Chem. Soc., 114 (1992) 10024.
Storer, J.W., Giesen, D.J., Cramer, C.J. and Truhlar, D.G., J. Comput.-Aided Mol. Des., 9 (1995) 87.
Dewar, M.J.S. and Thiel, W., J. Am. Chem. Soc., 99 (1977) 4899.
Stewart, J.J.P., J. Comput. Chem., 10 (1989) 209; ibid 10 (1989) 221.
Dewar, M.J.S., Zoebisch, E.G., Healy, E.F. and Stewart, J.J.P., J. Am. Chem. Soc., 107 (1985) 3902.
Jorgensen, W.L., Maxwell, D.S. and Tirado-Rives, J., J. Am. Chem. Soc., 118 (1996) 11225.
Leach, A.R., J. Mol. Biol., 235 (1994) 345.
Carlson, H.A., Curr. Opin. Chem. Biol., 6 (2002) 447.
Holland, J.H., Adaptation in Natural and Artificial Systems. MIT Press, Cambridge, MA, 1992.
Oshiro, C.M., Kuntz, I.D. and Dixon, J.S., J. Comput.-Aided Mol. Des., 9 (1995) 113.
Davis, M.E., Madura, J.D., Luty, B.A. and McCammon, J.A., Comp. Phys. Comm., 62 (1991) 187.
Woodcock, D. Molecule Models Web Site at http://people.ouc.bc.ca/woodcock/molecule/molecule.html, Okanagan University, British Columbia: 2002.
Schrödinger Inc., Jaguar 3.5. Schrödinger Inc., Portland, OR, 1998.
Williams, D.E., Rev. Comp. Chem., 2 (1991) 219.
Varghese, J.N., Epa, V.C. and Colman, P.M., Protein Sci., 4 (1995) 1081.
Smith P.W., Sollis S.L., Howes P.D., Cherry P.C., Cobley K.N., Taylor H., Whittington A.R., Scicinski J., Bethell R.C., Taylor N., Skarzynski T., Cleasby A., Singh O., Wonacott A., Varghese J. and Colmna P., Bioorg. Med. Chem. Lett., 6 (1996) 2931.
Taylor, N.R., Cleasby, A., Singh, O., Skarzynski, T., Wonacott, A.J., Smith, P.W., Sollis, S.L., Howes, P.D., Cherry, P.C., Bethell, R., Colman, P. and Varghese, J., J. Med. Chem., 41 (1998) 798.
Molecular Simulations Inc., Insight II. M+olecular Simulations Inc., San Diego, CA, 1993.
Eldridge, M.D., Murray, C.W., Auton, T.R., Paolini, G.V., and Mee, R.P., J. Comput.-Aided Mol. Des., 11 (1997) 425.
Mitchell, J.B.O., Laskowski, R.A., Alex, A., Forster, M.J. and Thornton, J.M., J. Comput. Chem., 20 (1999) 1177.
Jedrzejas, M.J., Singh, S., Brouillette, W.J., Laver, W.G., Air, G.M. and Luo, M., Biochemistry, 34 (1995) 3144.
Collard, P. and Clergue, M., Complex Systems, 12 (2000) 1.
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.
Pellegrini, E. and Field, M.J., J. Phys. Chem. A, 106 (2002) 1316.
Ghose, A.K., Viswanadhan, V.N. and Wendoloski, J.J., J. Phys. Chem. A, 102 (1998) 3762.
Muegge, I. and Martin, Y.C., J. Med. Chem., 42 (1999) 791.
Luo, Z., Wang, R. and Lai, L., J. Chem. Inf. Comput. Sci., 36 (1996) 1187.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pellegrini, E., Field, M.J. Development and testing of a de novo drug-design algorithm. J Comput Aided Mol Des 17, 621–641 (2003). https://doi.org/10.1023/B:JCAM.0000017362.66268.d5
Issue Date:
DOI: https://doi.org/10.1023/B:JCAM.0000017362.66268.d5