Journal of Computer-Aided Molecular Design

, Volume 18, Issue 10, pp 635–650 | Cite as

Unsupervised guided docking of covalently bound ligands

  • Xavier FraderaEmail author
  • Jasmit Kaur
  • Jordi Mestres


An approach for docking covalently bound ligands in protein enzymes or receptors was implemented in MacDOCK, a similarity-driven docking program based on DOCK 4.0. This approach was tested with a small number of covalent ligand–protein structures, using both native and non-native protein structures. In all cases, MacDOCK was able to generate orientations consistent with the known covalent binding mode of these complexes, with a performance similar to that of other docking programs. This method was also applied to search for known covalent thrombin inhibitors in a medium-sized molecular database (ca. 11,000 compounds). Detection of functional groups suitable for covalent docking was carried out automatically. A significant enrichment in known active molecules in the first 5% of the database was obtained, showing that MacDOCK can be used efficiently for the virtual screening of covalently bound ligands.


covalently bound ligands molecular similarity protein–ligand docking thrombin virtual screening 


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  1. Hajduk, P.J., Gerfin, T., Boehlen, J.-M., Häberli, M., Marek, D., Fesik, S.W. 1999J. Med. Chem.422315Google Scholar
  2. Blundell, T.L., Jhoti, H., Abell, C. 2002Nat. Rev. Drug Discov.145Google Scholar
  3. Savchenko, A., Yee, A., Khachatryan, A., Skarina, T., Evdokimova, E., Pavlova, M., Semesi, A., Northey, J., Beasley, S., Lan, N., Das, R., Gerstein, M., Arrowmith, C.H., Edwards, A.M. 2003Proteins50392Google Scholar
  4. Stevens, R.C., Yokoyama, S., Wilson, I.A. 2001Science29489Google Scholar
  5. Heinemann, U., Büssow, K., Mueller, U., Umbach, P. 2003Acc. Chem. Res.36157Google Scholar
  6. Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E. 2000Nucleic Acids Res.28235CrossRefGoogle Scholar
  7. Hendlich, M., Bergner, A., Günther, J., Klebe, G. 2003J. Mol. Biol.326607Google Scholar
  8. Fradera, X., Mestres, J. 2004Curr. Top. Med. Chem.4687Google Scholar
  9. Halperin, I., Ma, B., Wolfson, H., Nussinov, R. 2002Proteins47409Google Scholar
  10. Lyne, P.D. 2002Drug Discov. Today71047Google Scholar
  11. Jones, G., Willett, P., Glen, R.C., Leach, A.R., Taylor, R. 1997J. Mol. Biol.267727Google Scholar
  12. McMartin, C., Bohacek, R.S. 1997J. Comput.-Aided Mol. Design11333Google Scholar
  13. Kramer, B., Rarey, M., Lengauer, T. 1999Proteins37228CrossRefPubMedGoogle Scholar
  14. Gehlhaar, D.K., Bouzida, D., Rejto, P.A. 1999ACS Symp. Ser.719292Google Scholar
  15. Fradera, X., Knegtel, R.M.A., Mestres, J. 2000Proteins40623Google Scholar
  16. Ewing, T., Kuntz, I.D. 1997J. Comput. Chem.181175Google Scholar
  17. Mestres, J., Rohrer, D.C., Maggiora, G.M. 1997J. Comput. Chem.18934Google Scholar
  18. Weiner, S.J., Kollman, P.A., Hguyen, D.T., Case, D.A. 1986J. Comput. Chem.7230Google Scholar
  19. Maggiora, G.M., Petke, J.D., Mestres, J. 2002J. Math. Chem.31251Google Scholar
  20. Gasteiger, J., Marsili, M. 1980Tetrahedron363219Google Scholar
  21. Sadowski, J., Gasteiger, J., Klebe, G. 1994J. Chem. Inf. Comput. Sci.341000Google Scholar
  22. Knegtel, R.M.A., Bayada, D.M., Engh, R.A., Saal, W., Geerestein, V.J., Grootenhuis, P.D.J. 1999J. Comput.-Aided Mol. Design13167Google Scholar
  23. Knegtel, R.M.A., Wagener, M. 1999Proteins37334Google Scholar
  24. Baxter, C.A., Murray, C.W., Waszkowycz, B., Li, J., Sykes, R.A., Bone, R.G.A., Perkins, T.D.J., Wylie, W. 2000J. Chem. Inf. Comput. Sci.,40254Google Scholar
  25. Erickson, J.A., Jalaie, M., Robertson, D.H., Lewis, R.A., Vieth, M. 2004J. Med. Chem.4745Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  1. 1.Department of Medicinal ChemistryOrganon Laboratories Ltd.Newhouse, LanarkshireScotlandUK
  2. 2.OSI PharmaceuticalsOxfordUK
  3. 3.Institut Municipal d‘Investigació MèdicaUniversitat Pompeu FabraBarcelonaSpain

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