Summary
Significant improvements have been made to the de novo drug design program BUILDER. The BUILDER strategy is to find molecule templates that bind tightly to ‘hot spots’ in the target receptor, and then generate bridges to join these templates. In this paper, the bridging algorithm has been further developed to improve the chemical sense and diversity of the bridges, as well as the robustness of the technique. The improved algorithm is then applied to rebuild known bridges in methotrexate and HIV protease. Finally, the entire BUILDER approach is tested by rebuilding methotrexate de novo.
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Lam, P.Y.S., Jadhav, P.K., Eyermann, C.J., Hodge, C.N., Ru, Y., Bacheler, L.T., Meek, J.L., Otto, M.L., Rayner, M.M., Wong, Y.N., Chang, C.H., Weber, P.C., Jackson, D.A., Sharpe, T.R. and Erickson-Viitanen, S., Science, 263 (1994) 380.
Ring, C.S., Sun, E., McKerrow, J.H., Lee, G.K., Rosenthal, P.J., Kuntz, I.D. and Cohen, F.E., Proc. Natl. Acad. Sci. USA, 90 (1993) 3583.
DesJarlais, R.L., Seibel, G.L., Kuntz, I.D., Furth, P.S., Alvarez, J.C., Montellano, P.R., DeCamp, D.L., Babe, L.M. and Craik, C.S., Proc. Natl. Acad. Sci. USA, 87 (1990) 6644.
Appelt, K., Bacquet, R.J., Bartlett, C.A., Booth, C.L.J., Freer, S.T., Fuhry, M.A.M., Gehring, M.R., Herrmann, S.M., Howland, E.F., Janson, C.A., Jones, T.R., Kan, C.-C., Kathardekar, V., Lewis, K.K., Marzoni, G.P., Matthews, D.A., Mohr, C., Moomaw, E.W., Morse, C.A., Oatley, S.J., Ogden, R.C., Reddy, M.R., Reich, S.H., Schoettlin, W.S., Smith, W.W., Varney, M.D., Villafranca, J.E., Ward, R.W., Webber, S., Webber, S.E., Welsh, K.M. and White, J., J. Med. Chem., 34 (1991) 1925.
Shoichet, B.K., Stroud, R.M., Santi, D.V., Kuntz, I.D. and Perry, K.M., Science, 259 (1993) 1445.
Ripka, W.C., Sipio, W.J. and Galbraith, W.G., J. Cell Biochem., 40 (1989) 279.
Baldwin, J.J., Ponticello, G.S., Anderson, P.S., Christy, M.E., Murcko, M.A., Randall, W.C., Schwam, H., Sugrue, M.F., Springer, S.P., Gautheron, P., Grove, J., Mallorga, P., Viader, M., McKeever, B.M. and Navia, M.A., J. Med. Chem., 32 (1989) 2510.
Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.
Meng, E.C., Shoichet, B.K. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 505.
Lawrence, M.C. and Davis, P.C., Protein Struct. Funct. Genet., 12 (1992) 31.
Miller, M.D., Kearsley, S.K., Underwood, D.J. and Sheridan, R.P., J. Comput.-Aided Mol. Design, 8 (1994) 153.
Bacon, D.J. and Moult, J., J. Mol. Biol., 225 (1992) 849.
Itai, A. and Nishibata, Y., Tetrahedron, 47 (1991) 8985.
Itai, A. and Nishibata, Y., J. Med. Chem., 36 (1993) 2921.
Rotstein, S.H. and Murcko, M.A., J. Comput.-Aided Mol. Design, 7 (1993) 23.
Bohacek, R.S. and McMartin, C., J. Am. Chem. Soc., 116 (1994) 5560.
Moon, J.B. and Howe, J.W., Protein Struct. Funct. Genet., 11 (1991) 314.
Rotstein, S.H. and Murcko, M.A., J. Med. Chem., 36 (1993) 1700.
Gillet, V., Johnson, P., Mata, P., Sike, S. and Williams, P., J. Comput.-Aided Mol. Design, 7 (1993) 127.
Gillet, V.J., Newell, W., Mata, P., Myatt, G., Sike, S., Zsoldos, Z. and Johnson, A.P., J. Chem. Inf. Comput. Sci., 34 (1994) 207.
Goodford, P.J., J. Med. Chem., 28 (1985) 819.
Boobbyer, D.N., Goodford, P.J., McWhinnie, P.M. and Wade, R.C., J. Med. Chem., 32 (1989) 1083.
Danziger, D.J. and Dean, P.M., Proc. R. Soc. London Ser. B, 236 (1989) 114.
Danziger, D.J. and Dean, P.M., Proc. R. Soc. London, Ser. B, 236 (1989) 101.
Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 593.
Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.
Miranker, M. and Karplus, M., Protein Struct. Funct. Genet., 11 (1991) 29.
Pearlman, D.A. and Murcko, M.A., J. Comput. Chem., 14 (1993) 1184.
Ho, C.W. and Marshall, G.R., J. Comput.-Aided Mol. Design, 7 (1993) 3.
Bartlett, P.A., Shea, G.T., Telfer, S.J. and Waterman, S., In Molecular Recognition in Chemical and Biological Problems, Special Publication Vol. 78, Royal Chemical Society, London, 1989, p. 182.
Tschinke, V. and Cohen, N.C., J. Med. Chem., 36 (1993) 3863.
Ho, C.W. and Marshall, G.R., J. Comput.-Aided Mol. Design, 7 (1993) 623.
Leach, A.R. and Kilvington, S.R., J. Comput.-Aided Mol. Design, 8 (1994) 283.
Fine, R.M., Wang, H., Shenkin, P.S., Yarmush, D.L. and Levinthal, C., Protein Struct. Funct. Genet., 1 (1986) 342.
Shenkin, P.S., Yarmush, D.L., Fine, R.M., Wang, H. and Levinthal, C., Biopolymers, 26 (1987) 2053.
Lewis, R.A. and Dean, P.M., Proc. R. Soc. London Ser. B, 236 (1989) 125.
Lewis, R.A. and Dean, P.M., Proc. R. Soc. London Ser. B, 236 (1989) 141.
Lewis, R.A., J. Comput.-Aided Mol. Design, 4 (1990) 205.
Lewis, R.A., Roe, D.C., Huang, C., Ferrin, T.E., Langridge, R. and Kuntz, I.D., J. Mol. Graph., 10 (1992) 66.
Ferrin, T.E., Huang, C.c., Jarvis, L.E. and Langridge, R., J. Mol. Graph., 6 (1988) 13.
Van, Gunsteren, W.F. and Berendsen, H.J.C., Mol. Acc. Chem. Res. Phys., 34 (1977) 1311.
Ryckaert, J.P., Cicotti, G. and Berendsen, H.J.C., J. Comput. Phys., 23 (1977) 327.
Kabsch, W., Acta Crystallogr., A32 (1976) 922.
Kabsch, W., Acta Crystallogr., A33 (1978) 817.
Leach, A.R., Prout, K. and Dolata, D.P., J. Comput.-Aided Mol. Design, 2 (1988) 107.
Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.
Berntein, F.C., Koetzle, T.F., Williams, G.J., Meyer, E.E., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.
Erickson, J., Neidhart, D.J., VanDrie, J., Kempf, D.J., Wang, X.C., Norbeck, D.W., Plattner, J.J., Rittenhouse, J.W., Turon, M., Wideburg, N., Kohlbrenner, W.E., Simmer, R., Helfrich, R., Paul, D.A. and Knigge, M., Science, 249 (1990) 527.
Comprehensive Medicinal Chemistry Database, version 89.2. Available from Molecular Design Ltd., San Leandro, CA.
Kellogg, G.E., Semus, S.F. and Abraham, D.J., J. Comput.-Aided Mol. Design, 5 (1991) 545.
SYBYL, Version 6.03, Tripos Associates, St. Louis, MO, 1993.
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Roe, D.C., Kuntz, I.D. BUILDER v.2: Improving the chemistry of a de novo design strategy. J Computer-Aided Mol Des 9, 269–282 (1995). https://doi.org/10.1007/BF00124457
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DOI: https://doi.org/10.1007/BF00124457