Skip to main content
SpringerLink
Log in

Hydrophobicity maps and docking of molecular fragments with solvation

  • Chapter
Virtual Screening: An Alternative or Complement to High Throughput Screening?

Summary

Two methods for structure-based computational ligand design are reviewed. Hydrophobicity maps allow to quantitatively estimate and graphically display the propensity of nonpolar groups to bind at the surface of a protein target [Scarsi et al., Proteins Struct. Funct. Genet., 37 (1999) 565]. The program SEED (Solvation Energy for Exhaustive Docking) finds optimal positions and orientations of nonpolar fragments using the hydrophobicity maps, while polar fragments are docked with at least one hydrogen bond with the protein [Majeux et al., Proteins Struct. Funct. Genet., 37 (1999) 88]. An efficient evaluation of the binding energy, including continuum electrostatic solvation, allows to dock a library of 100 fragments into a 25-residue binding site in about five hours on a personal computer. Applications to thrombin, a key enzyme in the blood coagulation cascade, and the p38 mitogen-activated protein kinase, which is a target for the treatment of inflammatory and neurodegenerative diseases, are presented. The role of the hydrophobicity maps and structure-based docking of a fragment library in exploiting genomes to design drugs is addressed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Janin, J. and Chothia, C., J. Biol. Chem., 265 (1990) 16027.

    PubMed  CAS  Google Scholar 

  2. Janin, J. and Chothia, C., Biochemistry, 17 (1978) 2943.

    Article  PubMed  CAS  Google Scholar 

  3. Horton, N. and Lewis, M., Protein Sci., 1 (1992) 169.

    PubMed  CAS  Google Scholar 

  4. Young, L., Jernigan, R.L. and Covell, D.G., Protein Sci., 3 (1994) 717.

    PubMed  CAS  Google Scholar 

  5. Davis, A.M. and Teague, S.J., Angew. Chem. Int. Ed., 38 (1999) 736.

    Article  CAS  Google Scholar 

  6. Scarsi, M., Majeux, N. and Caflisch, A., Proteins Struct. Funct. Genet., 37 (1999) 565.

    PubMed  CAS  Google Scholar 

  7. Veerapandian, P., Structure-Based Drug Design, Marcel Dekker Inc., New York, NY, 1997.

    Google Scholar 

  8. Kubinyi, H., Curr. Opin. Drug Design Discov., 1 (1998) 4.

    CAS  Google Scholar 

  9. Caflisch, A., Walchli, R. and Ehrhardt, C., News Physiol. Sci., 13 (1998) 182.

    PubMed  CAS  Google Scholar 

  10. Böhm, H.J., Banner, D.W. and Weber, L., J. Comput.-Aided Mol. Design, 13 (1999) 51.

    Google Scholar 

  11. Caflisch, A. and Karplus, M., Perspect. Drug Discov. Design, 3 (1995) 51.

    CAS  Google Scholar 

  12. Majeux, N., Scarsi, M., Apostolakis, J., Ehrhard, C. and Caflisch, A., Proteins Struct. Funct. Genet., 37 (1999) 88.

    PubMed  CAS  Google Scholar 

  13. Scarsi, M., Apostolakis, J. and Caflisch, A., J. Phys. Chem. A, 101 (1997) 8098.

    Article  CAS  Google Scholar 

  14. Scarsi, M., Apostolakis, J. and Caflisch, A., J. Phys. Chem. B, 102 (1998) 3637.

    Article  CAS  Google Scholar 

  15. Caflisch, A., J. Comput.-Aided Mol. Design, 10 (1996) 372.

    CAS  Google Scholar 

  16. So, S. and Karplus, M., J. Comput.-Aided Mol. Design, 13 (1999) 243.

    CAS  Google Scholar 

  17. Apostolakis, J. and Caflisch, A., Comb. Chem. High Throughput Screening, 2 (1999) 91.

    CAS  Google Scholar 

  18. Cramer, C.J. and Truhlar, D.G., Chem. Rev., 99 (1999) 2161.

    Article  PubMed  CAS  Google Scholar 

  19. Roux, B. and Simonson, T., Biophys. Chem., 78 (1999) 1.

    Article  CAS  PubMed  Google Scholar 

  20. Lee, B. and Richards, F.M., J. Mol. Biol., 55 (1971) 379.

    Article  PubMed  CAS  Google Scholar 

  21. Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., J. Comput. Chem., 4 (1983) 187.

    Article  CAS  Google Scholar 

  22. Momany, F.A., Klimkowski, V.J. and Schäfer, L., J. Comput. Chem., 11 (1990) 654.

    Article  CAS  Google Scholar 

  23. Nicholls, A., Sharp, K.A. and Honig, B., Proteins Struct. Funct. Genet., 11 (1991) 281.

    PubMed  CAS  Google Scholar 

  24. Privalov, P.L. and Gill, S.G., Adv. Protein Chem., 39 (1988) 191.

    PubMed  CAS  Google Scholar 

  25. Privalov, P.L. and Gill, S.G., Adv. Protein Chem., 247 (1990) 559.

    Google Scholar 

  26. Creighton, T.E., Curr. Opin. Struct. Biol., 1 (1991) 5.

    CAS  Google Scholar 

  27. Friedman, R.A. and Honig, B., Biophys. J., 69 (1995) 1528.

    Article  PubMed  CAS  Google Scholar 

  28. Caflisch, A., Fischer, S. and Karplus, M., J. Comput. Chem., 18 (1997) 723.

    CAS  Google Scholar 

  29. Vorobjev, Y.N., Almagro, J.C. and Hermans, J., Proteins Struct. Funct. Genetics, 32 (1998) 399.

    Article  CAS  Google Scholar 

  30. Warwicker, J. and Watson, H.C., J. Mol. Biol., 157 (1982) 671.

    Article  PubMed  CAS  Google Scholar 

  31. Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., J. Am. Chem. SOC., 112 (1990) 6127.

    Article  CAS  Google Scholar 

  32. Hawkins, G.D., Cramer, C.J. and Trulhar, D.G., Chem. Phys. Lett., 246 (1995) 122.

    Article  CAS  Google Scholar 

  33. Hawkins, G.D., Cramer, C.J. and Trulhar, D.G., J. Phys. Chem., 100 (1996) 19824.

    Article  CAS  Google Scholar 

  34. Schaefer, M. and Karplus, M., J. Phys. Chem., 100 (1996) 1578.

    Article  CAS  Google Scholar 

  35. Di Qiu, Shenkin, P.S., Hollinger, F.P., and Still, W.C., J. Phys. Chem. A, 101 (1997) 3005.

    Article  CAS  Google Scholar 

  36. Jackson, J.D., Classical Electrodynamics, John Wiley & Sons, New York, NY, 1975.

    Google Scholar 

  37. Luo, R., Moult, J. and Gilson, M.K., J. Phys. Chem. B, 101 (1997) 11226.

    CAS  Google Scholar 

  38. Richards, F.M., Annu. Rev. Biophys. Bioeng., 6 (1977) 151.

    Article  PubMed  CAS  Google Scholar 

  39. Tapparelli, C., Metternich, R., Ehrhardt, C. and Cook, N.S., Trends Pharmacol Sci., 14 (1993) 366.

    PubMed  CAS  Google Scholar 

  40. Brandstetter, H., Turk, D., Hoeffken, H.W., Grosse, D., Stuerzebecher, J., Martin, D.P., Edwards, B.F.P. and Bode, W., J. Mol. Biol., 226 (1992) 1085.

    Article  PubMed  CAS  Google Scholar 

  41. Lee, J.C., Laydon, J.T., McDonnell, P.C., Gallagher, T.F., Kumar, S., Green, D., McNulty, D., Blumenthal, M.J., Heys, J.R., Landvatter, S.W. and Young, P.R., Nature, 372 (1994) 739.

    Article  PubMed  CAS  Google Scholar 

  42. Han, J., Lee, J.D., Bibbs, L. and Ulevitch, R.J., Science, 265 (1994) 808.

    PubMed  CAS  Google Scholar 

  43. Rouse, J., Cohen, P., Trigon, S., Morange, M., Alonso-Llamazares, A., Zamanillo, D., Hunt T. and Nebreda, A.R., Cell, 78 (1994) 1027.

    Article  PubMed  CAS  Google Scholar 

  44. Freshney, N.W., Rawlinson, L., Guesdon, F., Jones, E., Cowley, S., Hsuan, J. and Saklatvala, J., Cell, 78 (1994) 1039.

    Article  PubMed  CAS  Google Scholar 

  45. Cuenda, A., Rouse, J., Doza, Y.N., Meier, R., Cohen, P., Gallagher, T.F., Young, P.R. and Lee, L.C., FEBS Lett., 364 (1995) 229.

    Article  PubMed  CAS  Google Scholar 

  46. Lee, L.C. and Adams, J.L., Curr. Opin. Biotechnol., 6 (1995) 657.

    Article  PubMed  CAS  Google Scholar 

  47. Gallagher, T.F., Seibel, G.L., Kassis, S., Laydon, J.T., Blumenthal, M.J., Lee, J.C., Lee, D., Boehm, J.C., Fier-Thompson, S.M., Abt, J.W., Soreson, M.E., Smietana, J.M., Hall, R.F., Garigipati, R.S., Bender, P.E., Erhard, K.F., Krog, A.J., Hofmann, G.A., Sheldrake, P.L., McDonnell, P.C., Kumar, S., Young, P.R. and Adams, J.L., Bioorg. Med. Chem., 5 (1997) 49.

    PubMed  CAS  Google Scholar 

  48. Wang, Z., Canagarajah, B.J., Boehm, J.C., Kassisa, S., Cobb, M.H., Young, P.R., Abdel-Meguid, S., Adams, J.L. and Goldsmith, E.J., Structure, 6 (1998) 1117.

    PubMed  CAS  Google Scholar 

  49. Tong, L., Pav, S., White, D.M., Rogers, S., Crane, K.M., Cywin, C.L., Brown, M.L. and Pargellis, C.A., Nat. Struct. Biol., 4 (1997) 311.

    Article  PubMed  CAS  Google Scholar 

  50. Gilson, M. K. and Honig, B. H., Proteins Struct. Funct. Genet., 4 (1988) 7.

    PubMed  CAS  Google Scholar 

  51. Bashford, D. and Karplus, M., Biochemistry, 29 (1990) 10219.

    Article  PubMed  CAS  Google Scholar 

  52. Davis, M. E., Madura, J. D., Luty, B. A. and McCammon, J. A., Comput. Phys. Commun., 62 (1991) 187.

    CAS  Google Scholar 

  53. Marrone, T. J., Gilson, M. K. and McCammon, J. A., J. Phys. Chem., 100 (1996) 1439.

    Article  CAS  Google Scholar 

  54. Davis, M.E. and McCammon, J.A., J. Comput. Chem., 10 (1989) 386.

    Article  CAS  Google Scholar 

  55. Banner, D.W. and Hadvary, P., J. Biol. Chem., 266 (1991) 20085.

    PubMed  CAS  Google Scholar 

  56. Stubbs, M. T. and Bode, W., Perspect. Drug Discov. Design, 1 (1993) 431.

    Google Scholar 

  57. Hilpert, K., Ackermann, J., Banner, D.W., Gast, A., Gubemator, K., Hadvary, P., Labler, L., Müller, K., Schmid, G., Tschopp, T. and van de Waterbeemd, H., J. Med. Chem., 37 (1994) 3889.

    Article  PubMed  CAS  Google Scholar 

  58. Lyle, T.A., Perspect. Drug Discov. Design, 1 (1993) 453.

    Google Scholar 

  59. Tabernero, L., Chang, C.Y., Ohringer, S., Lau, W.F., Iwanowicz, E.J., Han, W.C., Wang, T.C., Seiler, S.M., Roberts, D.G.M. and Sack, J.S., J. Mol. Biol., 246 (1995) 14.

    PubMed  CAS  Google Scholar 

  60. Obst, U., Gramlich, V., Diederich, F., Weber, L. and Banner, D.W., Angew. Chem., 107 (1995) 1874.

    Google Scholar 

  61. Wagner, J., Kallen, J., Ehrhardt, C., Evenou, J. and Wagner, D., J. Med. Chem., 41 (1998) 3664.

    PubMed  CAS  Google Scholar 

  62. Kikumoto, R., Tamao, Y., Tezuka, T., Tonomura, S., Hara, H., Ninomiya, K., Hijikata, A. and Okamoto, S., Biochemistry, 23 (1984) 85.

    Article  PubMed  CAS  Google Scholar 

  63. Stürzebecher, J., Walsmann, P., Voigt, B. and Wagner, G., Thromb. Res., 36 (1984) 457.

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  65. 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 

  66. Baxter, C.A., Murray, C.W., Clark, D.E., Westhead, D.R. and Eldridge, M.D., Proteins Struct. Funct. Genet., 33 (1998) 367.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  69. 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 

  70. DesJarlais, R.L., Sheridan, R.P., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem., 29 (1986) 2149.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  73. Miranker, A. and Karplus, M., Proteins Struct. Funct. Genet., 11 (1991) 29.

    PubMed  CAS  Google Scholar 

  74. Caflisch, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.

    Article  PubMed  CAS  Google Scholar 

  75. Miranker, A. and Karplus, M., Proteins Struct. Funct. Genet., 23 (1995) 472.

    PubMed  CAS  Google Scholar 

  76. Grootenhuis, P.D.J. and Karplus, M., J. Comput.-Aided Mol. Design, 10 (1996) 1.

    Article  CAS  Google Scholar 

  77. Joseph-McCarthy, D., Hogle, J.M. and Karplus, M., Proteins Struct. Funct. Genet., 29 (1997) 32.

    PubMed  CAS  Google Scholar 

  78. Leclerc, F. and Karplus, M., Theor. Chem. Acc., 101 (1999) 131.

    CAS  Google Scholar 

  79. Kolossvary, I. and Guida, W.C., J. Am. Chem. Soc., 118 (1996) 5011.

    Article  CAS  Google Scholar 

  80. Klebe, G. and Mietzner, T., J. Comput.-Aided Mol. Design, 8 (1994) 583.

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  82. Sánchez, R. and Sali, A., Proc. Natl. Acad. Sci. USA, 95 (1998) 13597

    PubMed  Google Scholar 

  83. Shuker, H.B., Hajduk, P.J., Meadows, R.P. and Fesik, S.W., Science, 274 (1996) 1531.

    Article  PubMed  CAS  Google Scholar 

  84. Hajduk, P.J., Meadows, R.P. and Fesik, S.W., Science, 278 (1997) 497.

    Article  PubMed  CAS  Google Scholar 

  85. Mattos, C. and Ringe, D., Nat. Biotechnol., 14 (1996) 595.

    Article  PubMed  CAS  Google Scholar 

  86. Dill, K.A., Nature, 400 (1999) 309.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Zürich, Winterthurerstraβe 190, CH-8057, Zü, Switzerland

    Nicolas Majeux, Marco Carsi, Catherine Tenette-Souaille & Amedeo Caflisch

Authors
  1. Nicolas Majeux
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Carsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catherine Tenette-Souaille
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amedeo Caflisch
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Pharmaceutical Chemistry, Philipps University of Marburg, Marbacher Weg 6, D-35032, Marburg, Germany

    Gerhard Klebe

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Kluwer Academic Publishers

About this chapter

Cite this chapter

Majeux, N., Carsi, M., Tenette-Souaille, C., Caflisch, A. (2000). Hydrophobicity maps and docking of molecular fragments with solvation. In: Klebe, G. (eds) Virtual Screening: An Alternative or Complement to High Throughput Screening?., vol 20. Springer, Dordrecht. https://doi.org/10.1007/0-306-46883-2_9

Download citation

  • DOI: https://doi.org/10.1007/0-306-46883-2_9

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-0-7923-6633-1

  • Online ISBN: 978-0-306-46883-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation