Summary
SPROUT is a new computer program for constrained structure generation that is designed to generate molecules for a range of applications in molecular recognition. It uses artificial intelligence techniques to moderate the combinatorial explosion that is inherent in structure generation. The program is presented here for the design of enzyme inhibitors. Structure generation is divided into two phases: (i) primary structure generation to produce molecular graphs to fit the steric constraints; and (ii) secondary structure generation which is the process of introducing appropriate functionality to the graphs to produce molecules that satisfy the secondary constraints, e.g., electrostatics and hydrophobicity. Primary structure generation has been tested on two enzyme receptor sites; the p-amidino-phenyl-pyruvate binding site of trypsin and the acetyl pepstatin binding site of HIV-1 protease. The program successfully generates structures that resemble known substrates and, more importantly, the predictive power of the program has been demonstrated by its ability to suggest novel structures.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Martin, Y.C., J. Med. Chem., 35 (1992) 2145.
Martin, Y.C., J. Comput.-Aided Mol. Design, 3 (1989) 225.
Bartlett, P.A., Shea, G.T. and Telfer, S.J., In Roberts, S.M. (Ed.) Molecular Recognition: Chemical and Biological Problems, The Royal Society of Chemistry, London, 1989, pp. 182–196.
DesJarlais, R.L., Sheridan, R.P., Seibel, G.L., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem., 31 (1988) 722.
Martin, Y.C., Tetrahedron Comput. Method, 3 (1990) 15.
Lewis, R.A. and Dean, P.M., Proc. R. Soc. London Ser. B, 236 (1989) 125.
Lewis, R.A., J. Comput.-Aided Mol. Design, 4 (1990) 205.
Lewis, R.A., J. Mol. Graphics, 10 (1992) 131.
Nishibata, Y. and Itai, A., Tetrahedron, 47 (1991) 8985.
Moon, J.J. and Howe, W.J., Proteins Struct. Funct. Genet., 11 (1991) 314.
Böhm, J.J., J. Comput.-Aided Mol. Design, 6 (1992) 61.
Lewis, R.A., Roe, D.C., Huang, C., Ferrin, T.E., Langridge, R. and Kuntz, I.D., J. Mol. Graphics, 10 (1992) 66.
Verlinde, C.L.M.J., Rudenko, G. and Hol, W.G.J., J. Comput.-Aided Mol. Design, 6 (1992) 131.
Wipke, W.T., Pitman, M.C., Koehler, R.T., Kislin, B.S. and Anderson, G.D., Abstracts of Papers, 202nd National Meeting of the American Chemical Society, New York, NY, Fall 1991, American Chemical Society, Washington, DC, 1991.
Doweyko, A.M., J. Med. Chem., 31 (1988) 1396.
Cohen, N.C., Blaney, J.M., Humblet, C., Gund, P. and Barry, D.C., J. Med. Chem., 33 (1990) 883.
Nilsson, N.J., Principles of Artificial Intelligence, Springer-Verlag, Berlin, 1982.
Gillet, V.J., Johnson, A.P., Mota, P. and Sike, S., in preparation.
Danziger, D.J. and Dean, P.M., Proc. R. Soc. London Ser. B, 236 (1989) 101.
Tomioka, N., Itai, A. and Iitaka, Y., J. Comput.-Aided Mol. Design, 1 (1987) 197.
Richards, F.M., Annu. Rev. Biophys. Bioeng., 6 (1977) 151.
Williams, D.H., Cox, J.P.L., Doig, A.J., Gardner, M., Gerhard, U., Kaye, P.T., Lal, A.R., Nicholls, I.A., Salter, C.J. and Mitchell, R.C., J. Am. Chem. Soc., 113 (1991) 7020.
Mohamadi, F., Richards, N.G.J., Guida, W.C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Hendrickson, T. and Still, W.C., J. Comput. Chem., 11 (1990) 440.
Hagler, A.T., Huler, E. and Lifson, S., J. Am. Chem. Soc., 96 (1974) 5319.
Howard, A.E. and Kollman, P.A., J. Med. Chem., 31 (1988) 1669.
Saunders, M., Houk, K.N., Wu, Y., Still, W.C., Lipton, M., Chang, G. and Guida, W.C., J. Am. Chem. Soc., 112 (1990) 1419.
Goodsell, D.S. and Olson, A.J., Proteins Struct. Funct. Genet., 8 (1990) 195.
Guida, W.C., Bohacek, R.S. and Erion, M.D., J. Comput. Chem., 13 (1992) 214.
Marquart, M., Walter, J., Deisenhofer, J., Bode, W. and Huber, R., Acta Crystallogr. Sect B., 39 (1983) 480.
QUANTA, Polygen Corp., Waltham, MA 02154, U.S.A.
Fitzgerald, P.M.D., McKeever, B.M., van Middlesworth, J.F., Springer, J.P., Heimbach, J.C., Leu, C.-T., Herber, W.K., Dixon, R.A.F. and Darke, P.L., J. Biol. Chem., 265 (1990) 14209.
Teig, S.L., In Collier, H., (Ed.) Proceedings of the Montreux 1992 International Chemical Conference, Infonortics Ltd., Calne, U.K., 1992, pp. 195–208.
Goodford, P.J., J. Med. Chem., 28 (1985) 849.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gillet, V., Johnson, A.P., Mata, P. et al. SPROUT: A program for structure generation. J Computer-Aided Mol Des 7, 127–153 (1993). https://doi.org/10.1007/BF00126441
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00126441