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Virtual screening with solvation and ligand-induced complementarity

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Perspectives in Drug Discovery and Design

Abstract

We present our database-screening tool SLIDE, which is capable of screening large data sets of organic compounds for potential ligands to a given binding site of a target protein. Its main feature is the modeling of induced complementarity by making adjustments in the protein side chains and ligand upon binding. Mean-field theory is used to balance the conformational changes in both molecules in order to generate a shape-complementary interface. Solvation is considered by prediction of water molecules likely to be conserved from the crystal structure of the ligand-free protein, and allowing them to mediate ligand interactions, if possible, or including a desolvation penalty when they are displaced by ligand atoms that do not replace the lost hydrogen bonds.A data set of over 175 000 organic molecules was screened for potential ligands to the progesterone receptor, dihydrofolate reductase, and a DNA-repair enzyme. In all cases the screening time was less than a day on a Pentium II processor, and known ligands as well as highly complementary new potential ligands were found.

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References

  1. Welch, W., Ruppert, J. and Jain, A.N., Chem. Biol., 3 (1996) 449.

    Article  PubMed  CAS  Google Scholar 

  2. Rarey, M., Wefing, S. and Lengauer, T., J. Comput.-Aided Mol. Design, 10 (1996) 41.

    Article  CAS  Google Scholar 

  3. Rarey, M., Kramer, B., Lengauer, T. and Klebe, G., J. Mol. Biol., 261 (1996) 470.

    Article  PubMed  CAS  Google Scholar 

  4. Jorgensen, W.L., Science, 254 (1991) 954.

    PubMed  CAS  Google Scholar 

  5. Schnecke, V., Swanson, C.A., Getzoff, E.D., Tainer, J.A. and Kuhn, L.A., Proteins Struct. Funct. Genet., 33 (1998) 74.

    PubMed  CAS  Google Scholar 

  6. Betts. M.J. and Sternberg, J.E., Protein Eng., 12 (1999) 271.

    Article  PubMed  CAS  Google Scholar 

  7. Schnecke, V. and Kuhn, L., Proteins Struct. Funct. Genet., 2000 (manuscript submitted).

  8. Raymer, M.L., Sanschagrin, P.C., Punch, W.F., Venkataraman, S., Goodman, E.D. and Kuhn, L.A., J. Mol. Biol., 265 (1997) 445.

    Article  PubMed  CAS  Google Scholar 

  9. Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.

    Article  PubMed  CAS  Google Scholar 

  10. Meng, E.C., Shoichet, B.K. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 505.

    Article  CAS  Google Scholar 

  11. Shoichet, B.K. and Kuntz, I.D., Protein Eng., 6 (1993) 723.

    PubMed  CAS  Google Scholar 

  12. Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 61.

    Article  Google Scholar 

  13. Böhm, H.-J., J. Comput.-Aided Mol. Design, 6 (1992) 593.

    Article  Google Scholar 

  14. Böhm, H.-J., J. Comput.-Aided Mol. Design, 10 (1996) 265.

    Article  Google Scholar 

  15. Rarey, M., Kramer, B. and Lengauer, T., J. Comput.-Aided Mol. Design, 11 (1997) 369.

    Article  CAS  Google Scholar 

  16. Jones, G., Willett, P. and Glen, R.C., J. Mol. Biol., 245 (1995) 43.

    Article  PubMed  CAS  Google Scholar 

  17. Jones, G., Willett, P., Glen, R.C., Leach, A.R. and Taylor, R., J. Mol. Biol., 267 (1997) 727.

    Article  PubMed  CAS  Google Scholar 

  18. Morris, G.M., Goodsell, D.S., Huey, R. and Olson, A.J., J. Comput.-Aided Mol. Design, 10 (1996) 293.

    Article  CAS  Google Scholar 

  19. Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R.S., Hart, W.E., Belew, R.K. and Olson, A.J., J. Comput. Chem., 19(14) (1998) 1639.

    Article  CAS  Google Scholar 

  20. Kuntz, I.D., Meng, E.C. and Shoichet, B.K., Acc. Chem. Res., 27 (1994) 117.

    Article  CAS  Google Scholar 

  21. Fischer, D., Lin, S. L., Wolfson, H. L. and Nussinov, R., J. Mol. Biol., 248 (1995) 459.

    PubMed  CAS  Google Scholar 

  22. Ruppert, J., Welch, W. and Jain, A.N., Protein Sci., 6 (1997) 524.

    Article  PubMed  CAS  Google Scholar 

  23. Oshiro, C.M., Kuntz, I.D. and Scott Dixon, J., J. Comput.-Aided Mol. Design, 9 (1995) 113.

    Article  CAS  Google Scholar 

  24. Eisen, M.B., Wiley, D.C., Karplus, M. and Hubbard, R.E., Proteins Struct. Funct. Genet., 19 (1994) 199.

    Article  PubMed  CAS  Google Scholar 

  25. Shoichet, B.K., Stroud, R.M., Santi, D.V., Kuntz, I.D. and Perry, K.M., Science, 259 (1993) 1445.

    PubMed  CAS  Google Scholar 

  26. Böhm, H.-J., J. Comput.-Aided Mol. Design, 8 (1994) 623.

    Article  Google Scholar 

  27. Gschwend, D.A., Sirawaraporn, W., Santi, D.V. and Kuntz, I.D., Proteins Struct. Funct. Genet., 29 (1997) 59.

    PubMed  CAS  Google Scholar 

  28. Lorber, D.M. and Shoichet, B.K., Protein Sci., 7 (1998) 938.

    Article  PubMed  CAS  Google Scholar 

  29. Shoichet, B.K., Leach, A.R. and Kuntz, I.D., Proteins Struct. Funct. Genet., 34 (1999) 4.

    Article  PubMed  CAS  Google Scholar 

  30. Makino, S., Ewing, T.J.A. and Kuntz, I.D., J. Comput.-Aided Mol. Design, 13 (1999) 513.

    Article  CAS  Google Scholar 

  31. Leach, A.R., J. Mol. Biol., 235 (1994) 345.

    PubMed  CAS  Google Scholar 

  32. Jackson, R.M., Gabb, H.A. and Sternberg, M.J.E., J. Mol. Biol., 276 (1998) 265.

    Article  PubMed  CAS  Google Scholar 

  33. Totrov, M. and Abagyan, R., Proteins Struct. Funct. Genet., Supplement 1 (1997) 215.

    Google Scholar 

  34. Sandak, B., Wolfson, H.J. and Nussinov, R., Proteins Struct. Funct. Genet., 32 (1998) 159.

    Article  PubMed  CAS  Google Scholar 

  35. Knegtel, R.M.A., Kuntz, I.D. and Oshiro, C.M., J. Mol. Biol., 266 (1997) 424.

    Article  PubMed  CAS  Google Scholar 

  36. Wassserman, Z.R. and Hodge, C.N., Proteins Struct. Funct. Genet., 24 (1996) 227.

    Article  Google Scholar 

  37. Apostolakis, J., Plückthun, A. and Caflisch, A., J. Comput. Chem., 19 (1998) 21.

    Article  CAS  Google Scholar 

  38. Mangoni, M., Roccatano, D. and Di Nola, A., Proteins Struct. Funct. Genet., 35 (1999) 153.

    Article  PubMed  CAS  Google Scholar 

  39. Poornima, C.S. and Dean, P.M., J. Comput.-Aided Mol. Design, 9 (1995) 500.

    Article  CAS  Google Scholar 

  40. Poornima, C.S. and Dean, P.M., J. Comput.-Aided Mol. Design, 9 (1995) 513.

    Article  CAS  Google Scholar 

  41. Ladbury, J.E., Chem. Biol., 3 (1996) 973.

    Article  PubMed  CAS  Google Scholar 

  42. Sanschagrin, P.C. and Kuhn, L.A., Protein Sci., 7 (1998) 2054.

    Article  PubMed  CAS  Google Scholar 

  43. Rarey, M., Kramer, B. and Lengauer, T., Proteins Struct. Funct. Genet., 34 (1999) 17.

    Article  PubMed  CAS  Google Scholar 

  44. Lawrence, M.C. and Davis, P.C., Proteins Struct. Funct. Genet., 12 (1992) 31.

    Article  PubMed  CAS  Google Scholar 

  45. Toyoda, T., Brobey, R.K.B., Sano, G., Horii, T., Tomioka, N. and Itai, A., Biochem. Biophys. Res. Commun., 235 (1997) 515.

    Article  PubMed  CAS  Google Scholar 

  46. Horvath, D., J. Med. Chem., 40 (1997) 2412.

    Article  PubMed  CAS  Google Scholar 

  47. Burkhard, P., Taylor, P. and Walkinshaw, M.D., J. Mol. Biol., 277 (1998) 449.

    Article  PubMed  CAS  Google Scholar 

  48. Schnecke, V. and Kuhn, L.A., In Procs. ISMB 99, 7th Int. Conf. on Intelligent Systems for Molecular Biology, AAAI Press, Menlo Park, CA, 1999, pp. 242–251.

    Google Scholar 

  49. Kuhn, L.A., Swanson, C.A., Pique, M.E., Tainer, J.A. and Getzoff, E.D., Proteins Struct. Funct. Genet., 23 (1995) 536.

    Article  PubMed  CAS  Google Scholar 

  50. Duda, R.O. and Hart, P.E., Pattern Classification and Scene Analysis, John Wiley & Sons, New York, NY, 1973.

    Google Scholar 

  51. Eldridge, M.D., Murray, C.W., Auton, T.R., Paolini, G.V. and Mee, R.P., J. Comput.-Aided Mol. Design, 11 (1997) 425.

    Article  CAS  Google Scholar 

  52. Koehl, P. and Delarue, M., J. Mol. Biol., 239 (1994) 249.

    Article  PubMed  CAS  Google Scholar 

  53. Koehl, P. and Delarue, M., Curr. Opin. Struct. Biol., 6 (1996) 222.

    Article  PubMed  CAS  Google Scholar 

  54. Sadowski, J., Gasteiger, J. and Klebe, G., J. Chem. Inf. Comput. Sci., 34 (1994) 1000.

    Article  CAS  Google Scholar 

  55. Mol, C.D., Arvai, A.S., Slupphaug, G., Kavli, B., Alseth, I., Krokan, H.E. and Tainer, J.A., Cell, 80 (1995) 869.

    Article  PubMed  CAS  Google Scholar 

  56. Parikh, S.S., Mol, C.D., Slupphaug, G., Bharati, S., Krokan, H.E. and Tainer, J.A., EMBO J., 17 (1998) 5214.

    Article  PubMed  CAS  Google Scholar 

  57. Mol, C.D., Arvai, A.S., Sanderson, R.J., Slupphaug, G., Kavli, B., Krokan, H.E., Mosbaugh, D.W. and Tainer, J.A., Cell, 82 (1995) 701.

    Article  PubMed  CAS  Google Scholar 

  58. Heringa, J. and Argos, P., Proteins Struct. Funct. Genet., 37 (1999) 44.

    Article  PubMed  CAS  Google Scholar 

  59. Knegtel, R.M.A., Bayada, D.M., Engh, R.A., von der Saal, W., van Geerestein, V.J. and Grootenhuis, P.D.J., J. Comput.-Aided Mol. Design, 13 (1999) 167.

    Article  CAS  Google Scholar 

  60. Böhm, H.-J., J. Comput.-Aided Mol. Design, 8 (1994) 243.

    Article  Google Scholar 

  61. Böhm, H.-J., J. Comput.-Aided Mol. Design, 12 (1998) 309.

    Article  Google Scholar 

  62. Jain, A.N., J. Comput.-Aided Mol. Design, 10 (1996) 427.

    Article  CAS  Google Scholar 

  63. Head, R.D., Smythe, M.L., Opera, T.I., Waller, C.L., Green, S.M. and Marshall, G.R., J. Am. Chem. Soc., 118 (1996) 3959.

    Article  CAS  Google Scholar 

  64. Murray, C.W., Auton, T.R. and Eldridge, M.D., J. Comput.-Aided Mol. Design, 12 (1998) 503.

    Article  CAS  Google Scholar 

  65. Mügge, I. and Martin, Y.C., J. Med. Chem., 42(5) (1999) 791.

    Article  Google Scholar 

  66. Cody, V., Sutton, P.A. and Welsh, W.J., J. Am. Chem. Soc., 109 (1987) 4053.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Protein Structural Analysis and Design Laboratory, Department of Biochemistry, Michigan State University, East Lansing, MI, 48824-1319, U.S.A.

    Volker Schnecke & Leslie A. Kuhn

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  1. Volker Schnecke
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  2. Leslie A. Kuhn
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Schnecke, V., Kuhn, L.A. Virtual screening with solvation and ligand-induced complementarity. Perspectives in Drug Discovery and Design 20, 171–190 (2000). https://doi.org/10.1023/A:1008737207775

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