Journal of Computer-Aided Molecular Design

, Volume 8, Issue 3, pp 231–242 | Cite as

A shape- and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors

  • Renee L. DesJarlais
  • J. Scott Dixon
Research Papers

Summary

The program DOCK [1,2] has been used successfully to identify molecules which will bind to a specified receptor [3]. The original method ranks molecules based on their shape complementarity to the receptor site and relies on the chemist to bring the appropriate electrostatic or hydrogen bond properties into the molecular skeletons obtained in the search. This is useful when screening a small database of compounds, where it is not likely that molecules with both the correct shape and electrostatic properties will be found. As large databases are more likely to have redundant molecular shapes with a variety of functionality (e.g., members of a congeneric series), it would be useful to have a method which identifies molecules with both the correct shape and functionality. To this end we have modified the DOCK 1.0 method to target user-specified atom types to selected positions in the receptor site. The target sites can be chosen based on structural evidence, calculation or inspection. Targeted-DOCK improves the ability of the DOCK method to find the crystallographically determined binding mode of a ligand. Additionally, targeted-DOCK searches a database of small molecules at 100–1000 times the rate of DOCK 1.0, allowing more molecules to be screened and more sophisticated scoring schemes to be employed. Targeted-DOCK has been used successfully in the design of a novel non-peptide inhibitor of HIV-1 protease.

Key words

Ligand design Molecular shape DOCK Database searching 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.Google Scholar
  2. 2.
    DesJarlais, R.L., Sheridan, R.P., Seibel, G.L., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem., 31 (1988) 722.Google Scholar
  3. 3.
    Kuntz, I.D., Science, 257 (1992) 1078.Google Scholar
  4. 4.
    Moon, J.B. and Howe, W.J., Protein Struct. Funct. Genet., 11 (1991) 314.Google Scholar
  5. 5.
    Böhm, H.-J. J. Comput.-Aided Mol. Design, 6 (1992) 61.Google Scholar
  6. 6.
    Lewis, R.A., Roe, D.C., Huang, C., Ferrin, T.E., Langridge, R. and Kuntz, I.D., J. Mol. Graphics, 10 (1992) 66.Google Scholar
  7. 7.
    Meng, E.C., Shoichet, B.K. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 505.Google Scholar
  8. 8.
    Leach, A.R. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 730.Google Scholar
  9. 9.
    Chenera, B., DesJarlais, R.L., Finkelstein, J.P., Eggleston, D.S., Meek, T.D., TomaszekJr., T.A. and Dreyer, G.B., Bioorg. Med. Chem. Lett., 3 (1993) 2717.Google Scholar
  10. 10.
    Richards, F.M., Annu. Rev. Biophys. Bioeng. 6 (1977) 151.Google Scholar
  11. 11.
    Connoliy, M.I., Science, 221 (1983) 700.Google Scholar
  12. 12.
    Goodford, P.J., J. Med. Chem., 28 (1985) 849.Google Scholar
  13. 13.
    Miranker, A. and Karplus, M., Protein Struct. Funct. Genet., 11 (1991) 29.Google Scholar
  14. 14.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J., Meyer, E.F., Brice, M.D., Rodgers, J.R. Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.Google Scholar
  15. 15.
    Abola, E., Bernstein, F.C., Bryant, S.H., Koetzle, T.F. and Weng, J., In Allen, F.H., Bergerhoff, G. and Sievers, R. (Eds.) Crystallographic Database-Information Content, Software Systems, Scientific Applications, Data Commission of the International Union of Crystallography, Cambridge, 1987, p. 107.Google Scholar
  16. 16.
    Weis, W.I., Bruenger, A.T., Skehel, J.J. and Wiley, D.C., J. Mol. Biol., 212 (1990) 373.Google Scholar
  17. 17.
    Allen, F.H., Bellard, S.A., Brice, M.D., Cartwright, B.A. Doubleday, A., Higgs, H., Hummelink, T., Hummelink-Peters, B.G., Kennard, O., Motherwell, W.D.S., Rodgers, J.R. and Watson, D.G., Acta Crystallogr., B35 (1979) 2331.Google Scholar
  18. 18.
    Tronrud, D.E., Monzingo, A.F. and Matthews, B.W., Eur. J. Biochem., 157 (1986) 261.Google Scholar
  19. 19.
    Monzingo, A.F. and Matthews, B.W., Biochemistry, 23 (1984) 5724.Google Scholar
  20. 20.
    Holmes, M.A. and Matthews, B.W., Biochemistry, 20 (1981) 6912.Google Scholar
  21. 21.
    Holden, H.M., Tronrud, D.E., Monzingo, A.F., Weaver, L.H. and Matthews, B.W., Biochemistry, 26 (1987) 8542.Google Scholar
  22. 22.
    Tronrud, D.E., Holden, H.M. and Matthews, B.W., Science, 235 (1987) 571.Google Scholar
  23. 23.
    Debouck, C., AIDS Res. Hum. Retroviruses, 8 (1992) 153.Google Scholar
  24. 24.
    Wlodawer, A., Miller, M., Jaskolski, M., Sathyanarayana, B.K., Baldwin, E., Weber, I.T., Selk, I.M., Clawson, L., Schneider, J. and Kent, S.B.H., Science, 245 (1989) 616.Google Scholar
  25. 25.
    Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B.H. and Wlodawer, A., Science, 246 (1989) 1149.Google Scholar
  26. 26.
    Swain, A.L., Miller, M.M., Green, J., Rich, D.H., Kent, S.B.H. and Wlodawer, A., Proc. Natl. Acad. Sci. USA, 87 (1990) 8805.Google Scholar
  27. 27.
    Erickson, J., Neidhart, D.J., Van, Drie, 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.Google Scholar
  28. 28.
    Jaskolski, M., Tomasselli, A.G., Sawyer, T.K., Staples, D.G., Heinrikson, R.L., Schneider, J., Kent, S.B.H. and Wlodawer, A., Biochemistry, 30 (1991) 1600.Google Scholar
  29. 29.
    Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.Google Scholar
  30. 30.
    Dreyer, G.B., Lambert, D.M., Meek, T.D., Carr, T.J., TomaszekJr., T.A., Fernandez, A.V., Bartus, H., Cacciavillani, E., Hassell, A.M., Mimmich, M., PettewayJr., S.R., Metcalf, B.W. and Lewis, M., Biochemistry, 31 (1992) 6646.Google Scholar
  31. 31.
    Dreyer, G.B., Boehm, J.C., Chenera, B., DesJarlais, R.L., Hassell, A.M., Meek, T.D., TomaszekJr., T.A. and Lewis, M., Biochemistry, 32 (1993) 937.Google Scholar
  32. 32.
    RusinkoIII, A., Skell, J.M., Balducci, R., McGarity, C.M. and Pearlman, R.S., CONCORD, University of Texas, Austin, TX and Tripos Associates, St. Louis, MO, 1988.Google Scholar
  33. 33.
    Sauter, N.K., Bednarski, M.D., Wurzburg, B.A., Hanson, J.E., Whitesides, G.M., Skehel, J.J. and Wiley, D.C., Biochemistry, 28 (1989) 8388.Google Scholar
  34. 34.
    Weiner, P.K. and Kollman, P.A., J. Comput. Chem., 2 (1981) 287.Google Scholar
  35. 35.
    Seibel, G.L., AMBER, Version 3.0A, University of California, San Francisco, CA, 1989.Google Scholar
  36. 36.
    Lawrence, M.C. and Davis, P.C., Protein Struct. Funct. Genet., 12 (1992) 31.Google Scholar
  37. 37.
    Shoichet, B.K., Bodian, D.L. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 380.Google Scholar
  38. 38.
    Lam, P.Y.S., Jadhav, P.K., Eyermann, C.J., Hodge, C.N., Ru, Y., Bacheler, L.T., Meek, J.L., Otto, M.J., 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.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1994

Authors and Affiliations

  • Renee L. DesJarlais
    • 1
  • J. Scott Dixon
    • 1
  1. 1.Department of Physical and Structural ChemistrySmith Kline Beecham PharmaceuticalsKing of PrussiaU.S.A.

Personalised recommendations