Summary
Recent advances in a new method for the de novo design of enzyme inhibitors are reported. A new set of rules to define the possible nonbonded contacts between protein and ligand is presented. This method was derived from published statistical analyses of nonbonded contacts in crystal packings of organic molecules and has been implemented in the recently described computer program LUDI. Moreover, LUDI can now append a new substituent onto an already existing ligand. Applications are reported for the design of inhibitors of HIV protease and dihydrofolate reductase. The results demonstrate that LUDI is indeed capable of designing new ligands with improved binding when compared to the reference compound.
Similar content being viewed by others
References
Goodford, P.J., J. Med. Chem., 28 (1985) 849.
Boobbyer, D.N.A., Goodford, P.J., MCWhinnie, P.M. and Wade, R.C., J. Med. Chem., 32 (1989) 1083.
Miranker, A. and Karplus, M., Proteins 11 (1991) 29.
DesJarlais, R.L., Sheridan, R.P., Seibel, G.L., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem. 31 (1988) 722.
Lawrence, M.C. and Davis, P.C., Proteins 12 (1992) 31.
Bartlett, P.A., Shea, G.T., Telfer, S.J. and Waterman, S.. In: Roberts, S.M. (Ed.), Molecular Recognition: Chemical and Biological Problems, Royal Society of London, London, 1989, pp. 182–196.
Moon, J.B. and Howe, W.J., Proteins 11 (1991) 314.
Lewis, R.A., J. Comput. Aided Mol. Design, 4 (1990) 205.
Böhm, H.-J., J. Comput. Aided Mol. Design., 6 (1992) 61.
Allen, F.H., Kennard, O. and Taylor, R., Acc. Chem. Res. 16 (1983) 146.
Allen, F.H., Bellard, S., Brice, M.D., Cartwright, B.A., Doubleday, A., Higgs, V., Hummeling-Peters, T., Kennard, O., Motherwell, W.D.S., Rodgers, J.R. and Watson, D.G., Acta Crystallogr. B 35 (1979) 2331.
Murray-Rust, P. and Glusker, J.P., J. Am. Chem. Soc. 106 (1984) 1018.
Taylor, R. and Kennard, O., Acc. Chem. Res., 17 (1984) 320.
Vedani, A. and Dunitz, J.D., J. Am. Chem. Soc. 107 (1985) 7653.
Görbitz, C.H., Acta Crystallorgr., B45 (1989) 390.
Klebe, G., Habilitationsschrift. University of Heidelberg, 1991.
Görbitz, C.H. and Etter, M.C., J. Am. Chem. Soc. 114 (1992) 627.
Baker, E.N. and Hubbard, R.E., Progr. Biophys. Mol. Biol 44 (1984) 97.
Kroon, J., Kanters, J.A., Van Duijneveldt-Van de Rijdt, J.G.C.M., Van Duijneveldt, F.B. and Vliegenhardt, J.A., J. Mol. Struct., 24 (1975) 109.
Fersht, A.R., Shi, J.P., Knill-Jones, J., Lowe, D.M., Wilkinson, A.J., Blow D.M., Brick, P., Carter, P., Waye, M.M.Y. and Winter, G., Nature 314 (1985) 235.
Richards, F.M., Ann. Rev. Biophys. Bioeng. 6 (1977) 151.
Huff, J.R., J. Med. Chem. 34 (1991) 1834.
Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B.H. and Wlodawer, S., Science 246 (1989) 1149.
Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer Jr., E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, T., J. Mol. Biol. 112 (1977) 535.
DeSolms, S.J., Giuliani, E.A., Guare, J.P., Vacca, J.P., Sanders, W.M., Graham, S.L., Wiggins, J.M., Darke, P.L., Sigal, I.S., Zugay, J.A., Emini, E.A., Schleif, W.A., Quintero, J.C., Anderson, P.S. and Huff, J.R., J. Med. Chem. 34 (1991) 2852.
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.
Program INSIGHT, distributed by BIOSYM Technologies, San Diego, CA 92121, U.S.A.
Dauber-Osguthorpe, P., Roberts, V.A., Osguthorpe, D.J., Wolff, J. Genest, M. and Hagler, A.T., Proteins, 4 (1988) 31.
Bolin, J.T., Filman, D.A., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.
Blaney, J.M., Hansch, C., Silipo, C. and Villon, A., Chem. Rev. 84 (1984) 333.
Mitchell, J.B.O. and Price, S.L., Chem. Phys. Lett., 154 (1989) 267.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Böhm, HJ. LUDI: rule-based automatic design of new substituents for enzyme inhibitor leads. J Computer-Aided Mol Des 6, 593–606 (1992). https://doi.org/10.1007/BF00126217
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00126217