A genetic algorithm for the automated generation of small organic molecules: Drug design using an evolutionary algorithm

Journal of Computer-Aided Molecular Design - Tập 14 - Trang 449-466 - 2000
Dominique Douguet1, Etienne Thoreau1, Gérard Grassy2
1GALDERMA R&D, Sophia Antipolis Cedex, Valbonne, France
2Centre de Biochimie Structurale, UMR CNRS 9955, INSERM U414, Université Montpellier I, Faculté de Pharmacie, Montpellier Cedex, France

Tóm tắt

Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a novel tool for the investigation of such problems. These are a class of algorithms that mimic some of the major characteristics of Darwinian evolution. LEA has been designed in order to conceive novel small organic molecules which satisfy quantitative structure-activity relationship based rules (fitness). The fitness consists of a sum of constraints that are range properties. The algorithm takes an initial set of fragments and iteratively improves them by means of crossover and mutation operators that are related to those involved in Darwinian evolution. The basis of the algorithm, its implementation and parameterization, are described together with an application in de novo molecular design of new retinoids. The results may be promising for chemical synthesis and show that this tool may find extensive applications in de novo drug design projects.

Từ khóa


Tài liệu tham khảo

Walters, W.P., Stahl, M.T. and Murcko, M.A., Drug Des. Today, 3 (1998) 160.

Ghose, A.K., Viswanadhan, V.N. and Wendoloski, J.J., J. Comb. Chem., 1 (1999) 55.

Lewis, R.A., Mason, J.S. and McLay, I.M., J. Chem. Inf. Comput. Sci., 37 (1997) 599.

Darwin, C., The Origin of Species, Dent Gordon, London, 1973.

Fogel, L.J., Owens, A.J. and Walsh, M.J., Artificial Intelligence through Simulated Evolution, John Wiley & Sons, New York, NY, 1966.

Rechenberg, I., Cybernetic solution path of an experimental problem, Royal Aircraft Establishment Transl., No 1122, B.F. Toms, Transl. (Ministry of Aviation, Royal Aircraft Establishment), Farnborough, Hants., U.K., 1965.

Clark, D.E. and Westhead, D.R., J. Comput.-Aided Mol. Design, 10 (1996) 337.

Hibbert, D.B., Chemomet. Intell. Lab. Syst., 31 (1996) R5.

Schneider, G. and Schrödl, W., Proc. Natl. Acad. Sci. USA, 95 (1998) 12179.

Parrill, A.L., Drug Des. Today, 1 (1996) 12.

Holland, J., Adaptation in Natural and Artificial Systems (second edition), M.I.T. Press, Cambridge, MA, 1992.

Forrest, S., Science, 261 (1993) 872.

Goldberg, D.E., Genetic Algorithms in Search, Optimization, and Machine Learning, Addison-Wesley, Reading, MA, 1989.

Glen, R.C. and Payne, A.W.R., J. Comput.-Aided Mol. Design, 9 (1995) 181.

LeapFrog, Tripos Inc., St Louis, MO, U.S.A.

Westhead, D.R., Clark, D.E., Frenkel, D., Li, J., Murray, C.W., Robson, B. and Waszkowycz, B., J. Comput.-Aided Mol. Design, 9 (1995) 139.

Blaney, J.M., Dixon, J.S. and Weininger, D., Molecular Graphics Society Meeting on Binding Sites: Characterising and Satisfying Steric and Chemical Restraints, York, U.K., March 1993. Weininger, D., WO95/01606.

Weininger, D., J. Chem. Inf. Comput. Sci., 30 (1990) 237.

Bemis, G.W. and Murcko, M.A., J. Med. Chem., 39 (1996) 2887.

Lucasius, C.B. and Kateman, G., Chemometr. Intell. Lab. Syst., 19 (1993) 1.

Davis, L., In J.D. Schaffer (Ed.), Proceedings of the Third International Conference on Genetic Algorithms and Their Applications, San Mateo, CA, Morgan Kaufmann, 1989, pp. 61–69.

Rishton, G.M., Drug Des. Today, 2 (1997) 382.

Weber, L., Wallbaum, S., Broger, C. and Gubernator, K., Angew. Chem. Int. Ed. Engl., 34 (1995) 2280.

Singh, J., Ator, M.A., Jaeger, E.P., Allen, M.P., Whipple, D.A., Soloweij, J.E., Chowdhary, S. and Treasurywala, A.M., J. Am. Chem. Soc., 118 (1996) 1669.

Grassy, G., Fagart, J., Calas, B., Adenot, M., Rafestin-Obelin, M.E. and Auzou, G., Eur. J. Med. Chem., 32 (1997) 869.

Grassy, G., Trappe, P., Bompart, J., Calas, B. and Auzou, G., J. Mol. Graphics, 13 (1995) 356.

Grassy, G., Yasri, A., Buelow, R., Kaczorek, M. and Calas, B., Actualités de Chimie Thérapeutique, 24, 1998.

Grassy, G., Calas, B., Yasri, A., Lahana, R., Woo, J., Lyer, S., Kaczorek, M., Floc'h, R. and Buelow, R., Nat. Biotech., 16 (1998) 748.

McFarland, J.W. and Gans, D.J., J. Med. Chem., 29 (1986) 505.

Douguet, D., Thoreau, E. and Grassy, G., Quant. Struct.-Act. Relat., 18 (1999) 107.

Chambon, P., Faseb J., 10 (1996) 940.

Klaholz, B.P., Renaud, J.P., Mitschler, A., Zusi, C., Chambon, P., Gronemeyer, H. and Moras, D., Nat. Struct. Biol., 5 (1998) 199.

Ostrowski, J., Roalsvig, T., Hammer, L., Marinier, A., Starrett, J.E. Jr, Yu, K.-L. and Reczek, P.R., J. Biol. Chem., 273 (1998) 6, 3490.

DeJong, K., Machine Learning, 3 (1988) 121.

Sammon, J.W., IEEE Trans. Comput., C-18 (1969) 401.

Wall, L., Christiansen, T. and Schwartz, R.L., Programming Perl, O'Reilly.

RasMol v2.5, Sayle, R., Biomolecular Structure, Glaxo Research and Development, Greenford, Middlesex, U.K., 1994.

InsightII, Molecular Simulations Inc., San Diego, CA.

VAMP, Oxford Molecular Ltd, Oxford, U.K.

CORINA, Oxford Molecular Ltd, Oxford, U.K.

Sybyl, Tripos Associates, St. Louis, MO.

Silla, E., Tunon, I. and Pascual-Ahuir, J.L., J. Comput. Chem., 12 (1991) 1077. QCPE #554.

Suzuki, T., J. Comput.-Aided Mol. Design, 4 (1990) 155. QCPE #608. CHEMICALC-2.

Tuson, A. and Ross, P., Evol. Comput., 6 (1998) 161.

Hibbert, D.B., Chemometr. Intell. Lab. Syst., 19 (1993) 277.

Venkatasubramanian, V., Chan, K. and Caruthers, J.M., J. Chem. Inf. Comput. Sci., 35 (1995) 188.

Sundaram, A. and Venkatasubramanian, V., J. Chem. Inf. Comput. Sci., 38 (1998) 1177.

Brodmeier, T. and Pretsch, E., J. Comput. Chem., 15 (1994) 588.

Schwefel, H., Evolution and Optimum Seeking, Wiley, New York, NY, 1995.

Osman, I.H., Operational Research Tutorial Papers, Operational Research Society Press, Birmingham, U.K., 1995.

Thông tin
Thông tin xuất bản

Journal of Computer-Aided Molecular Design

Tập 14

449-466

Thông tin tác giả