Abstract
For the successful identification and docking of new ligands to a protein target by virtual screening, the essential features of the protein and ligand surfaces must be captured and distilled in an efficient representation. Since the running time for docking increases exponentially with the number of points representing the protein and each ligand candidate, it is important to place these points where the best interactions can be made between the protein and the ligand. This definition of favorable points of interaction can also guide protein structure-based ligand design, which typically focuses on which chemical groups provide the most energetically favorable contacts. In this paper, we present an alternative method of protein template and ligand interaction point design that identifies the most favorable points for making hydrophobic and hydrogen–bond interactions by using a knowledge base. The knowledge-based protein and ligand representations have been incorporated in version 2.0 of SLIDE and resulted in dockings closer to the crystal structure orientations when screening a set of 57 known thrombin and glutathione S–transferase (GST) ligands against the apo structures of these proteins. There was also improved scoring enrichment of the dockings, meaning better differentiation between the chemically diverse known ligands and a ∼15,000-molecule dataset of randomly-chosen small organic molecules. This approach for identifying the most important points of interaction between proteins and their ligands can equally well be used in other docking and design techniques. While much recent effort has focused on improving scoring functions for protein-ligand docking, our results indicate that improving the representation of the chemistry of proteins and their ligands is another avenue that can lead to significant improvements in the identification, docking, and scoring of ligands.
Similar content being viewed by others
References
Schnecke, V. and Kuhn, L.A., Perspectives in Drug Discovery and Design, 20 (2000) 171.
Schnecke, V. and Kuhn, L.A., Intell. Syst. Mol. Biol., (1999) 242.
Schnecke, V. and Kuhn, L.A., Thorpe, M.F. and Duxbury, P.M. (Eds.) Rigidity Theory and Applications, Kluwer Academic/ Plenum Publishers, New York, NY, 1999, pp. 385–400.
Schnecke, V., Swanson, C.A., Getzoff, E.D., Tainer, J.A. and Kuhn, L.A., Proteins, 33 (1998) 74.
Hobohm, U. and Sander, C., Protein Sci., 3 (1994) 522.
Raymer, M.L., Sanschagrin, P.C., Punch, W.F., Venkataraman, S., Goodman, E.D. and Kuhn, L.A., J. Mol. Biol., 265 (1997) 445.
Ippolito, J.A., Alexander, R.S. and Christianson, D.W.J., Mol. Biol., 215 (1990) 457.
McDonald, I. and Thornton, J.M., Atlas of Side-Chain and Main-Chain Hydrogen Bonding, http://www.biochem.ucl.ac.uk/?mcdonald/atlas/.
Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.
Shoichet, B.K. and Kuntz, I.D., Protein Eng., 6 (1993) 723.
Jones, G., Willett, P. and Glen, R.C., J. Mol. Biol., 245 (1995) 43.
Jones, G, Willett, P., Glen, R.C., Leach, A.R. and Taylor, R., J. Mol. Biol., 267 (1997) 727.
Ruppert, J., Welch, W. and Jain, A.N., Protein Sci., 6 (1997) 524.
Kramer, B., Rarey, M. and Lengauer, T., Proteins, 37 (1999) 228.
Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K. and Olson, A.J., J. Comp. Chem., 19 (1998) 1639.
Boobbyer, D.N., Goodford, P.J., McWhinnie, P.M. and Wade, R.C., J. Med. Chem., 32 (1989) 1083.
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E., Nucleic Acids Research, 28 (2000) 235.
Allen, F.H. and Kennard, O., Chemical Design Automation News, 8 (1993) 1& 31.
Bergner, A., Günther, J., Hendlich, M., Klebe, G. and Verdonk, M., Biopolymers, 61 (2002), 99.
Gohlke, H., Hendlich, M. and Klebe, G., J. Mol. Biol., 295 (2000) 337.
Gohlke, H., Hendlich, M. and Klebe, G., Perspectives in Drug Discovery and Design, 20 (2000) 115.
Verdonk, M.L., Cole, J.C., Watson, P., Gillet, V. and Willett, P., J. Mol. Biol., 307 (2001) 841.
Boer, D.R., Kroon, J., Cole, J.C., Smith, B. and Verdonk, M.L., J. Mol. Biol., 312 (2001) 275.
Moreno, E. and Leon, K., Proteins, 47 (2002) 1.
Sanschagrin, P. and Kuhn, L.A., Protein Sci., 7 (1998) 2054.
Dekker, R.J., Eichinger, A., Stoop, A.A., Bode, W., Pannekoek, H. and Horrevoets, A.J.G., J.Mol.Biol., 293 (1999) 613.
Oakley, A.J., Lo Bello, M., Ricci, G., Federici, G. and Parker, M.W., Biochemistry, 37 (1998) 9912.
Oakley, A.J., Rossjohn, J., Lo Bello, M., Caccuri, A.M., Federici, G. and Parker, M.W., Biochemistry, 36 (1997) 576.
Oakley, A.J., Lo Bello, M., Nuccetelli, M., Mazzetti, A.P. and Parker, M.W., J. Mol. Biol., 291 (1999) 913.
Prade, L., Huber, R., Manoharan, T.H., Fahl, W.E. and Reuter, W., Structure, 5 (1997) 1287.
Bissantz, C., Folkers, G. and Rognan, D., J. Med. Chem., 43 (2000) 4759.
Charifson, P.S., Corkery, J.J., Murcko, M.A. and Walters, W.P., J. Med. Chem., 42 (1999) 5100.
Stahl, M. and Rarey, M., J. Med. Chem., 44 (2001) 1035.
Baxter, C.A., Murray, C.W., Waszkowycz, B., Li, J., Sykes, R.A., Bone, R.G., Perkins, T.D. and Wylie, W. J., Chem. Inf. Comput. Sci., 40 (2000) 254.
Knegtel, R.M., Bayada, D.M., Engh, R.A., von der Saal, W., van Geerestein, V.J. and Grootenhuis, P.D., J. Comput. Aided. Mol. Des., 13 (1999) 167.
Knegtel, R.M. and Wagener, M., Proteins, 37 (1999) 334.
Fradera, X., Knegtel, R.M. and Mestres, J., Proteins, 40 (2000) 623.
Fox, T. and Haaksma, E.E., J. Comput. Aided. Mol. Des., 14 (2000) 411.
Sotriffer, C.A., Gohlke, H. and Klebe, G., J. Med. Chem., 45 (2002) 1967.
Murray, C.W., Baxter, C.A. and Frenkel, A.D., J. Comput. Aided. Mol. Des., 13 (1999) 547.
Mestres, J., Rohrer, D.C. and Maggiora, G.M., J. Comp. Chem., 18 (1997) 934.
Sadowski, J. and Gasteiger, J., Chem. Rev., 93 (1993) 2567.
Chen, Y.Z. and Ung, C.Y., J. Mol. Graph. Model., 20 (2001) 199.
Koehler, R.T., Villar, H.O., Bauer, K.E. and Higgins, D.L., Proteins, 28 (1997) 202.
Connolly, M.L., J. Mol. Graphics, 11 (1993) 139.
Weir, M.P., Bethell, S.S., Cleasby, A., Campbell, C.J., Dennis, R.J., Dix, C.J., Finch, H., Jhoti, H., Mooney, C.J., Patel, S., Tang, C.M., Ward, M., Wonacott, A.J. and Wharton, C.W., Biochemistry, 37 (1998) 6645.
Böhm, H.-J., J. Comput. Aided Mol Design, 6 (1992) 61.
Fischer, D., Norel, R., Wolfson, H. and Nussinov, R., Proteins, 16 (1993) 278.
Fischer, D., Lin, S.L., Wolfson, H.L. and Nussinov, R., J. Mol. Biol. 248 (1995), 459.
Kuhn, L.A., Swanson, C.A., Pique, M.E., Tainer, J.A., Getzoff, E.D., Proteins, 23 (1995), 536.
Author information
Authors and Affiliations
Additional information
(These authors contributed equally to this work)
Rights and permissions
About this article
Cite this article
Zavodszky, M.I., Sanschagrin, P.C., Kuhn, L.A. et al. Distilling the essential features of a protein surface for improving protein-ligand docking, scoring, and virtual screening. J Comput Aided Mol Des 16, 883–902 (2002). https://doi.org/10.1023/A:1023866311551
Issue Date:
DOI: https://doi.org/10.1023/A:1023866311551