Journal of Computer-Aided Molecular Design

, Volume 12, Issue 4, pp 309–309

Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs

  • Hans-Joachim Böhm
Article

Abstract

A dataset of 82 protein–ligand complexes of known 3D structure and binding constant Ki was analysed to elucidate the important factors that determine the strength of protein–ligand interactions. The following parameters were investigated: the number and geometry of hydrogen bonds and ionic interactions between the protein and the ligand, the size of the lipophilic contact surface, the flexibility of the ligand, the electrostatic potential in the binding site, water molecules in the binding site, cavities along the protein–ligand interface and specific interactions between aromatic rings. Based on these parameters, a new empirical scoring function is presented that estimates the free energy of binding for a protein–ligand complex of known 3D structure. The function distinguishes between buried and solvent accessible hydrogen bonds. It tolerates deviations in the hydrogen bond geometry of up to 0.25 Å in the length and up to 30 °Cs in the hydrogen bond angle without penalizing the score. The new energy function reproduces the binding constants (ranging from 3.7 × 10-2 M to 1 × 10-14 M, corresponding to binding energies between -8 and -80 kJ/mol) of the dataset with a standard deviation of 7.3 kJ/mol corresponding to 1.3 orders of magnitude in binding affinity. The function can be evaluated very fast and is therefore also suitable for the application in a 3D database search or de novo ligand design program such as LUDI. The physical significance of the individual contributions is discussed.

de novo design protein–ligand interactions scoring functions 

Referenc es

  1. 1.
    Lewis, R.A. and Leach, A.R., J. Comput.-Aided Mol. Design, 8 (1994) 467.Google Scholar
  2. 2.
    Nishibata, Y. and Itai, A., J. Med. Chem., 36 (1993) 2921.Google Scholar
  3. 3.
    Bohacek, R.S. and McMartin, C., J. Am. Chem. Soc., 116 (1994) 5560.Google Scholar
  4. 4.
    Gehlhaar, D.K., Moerder, K.E., Zichi, D., Sherman, C.J., Ogden, R.C. and Freer, S.T., J. Med. Chem., 38 (1995) 466.Google Scholar
  5. 5.
    Moon, J.B. and Howe, W.J., Proteins, 11 (1991) 314.Google Scholar
  6. 6.
    Tschinke, V. and Cohen, N.C., J. Med. Chem., 36 (1993) 3863.Google Scholar
  7. 7.
    Rotstein, S.H. and Murcko, M.A., J. Med. Chem., 36 (1993) 1700.Google Scholar
  8. 8.
    Eisen, M.B., Wiley, D.C., Karplus, M. and Hubbard, R.E., Proteins, 19 (1994) 199.Google Scholar
  9. 9.
    Caflish, A., Miranker, A. and Karplus, M., J. Med. Chem., 36 (1993) 2142.Google Scholar
  10. 10.
    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
  11. 11.
    Mata, P., Gillet, V.J., Johnson, P., Lampreia, J., Myatt, G.J., Sike, S. and Stebbings, A.L., J. Chem. Inf. Comput. Sci., 35 (1995) 479.Google Scholar
  12. 12.
    Bartlett, P.A., Shea, G.T., Telfer, S.J. and Waterman, S., In Roberts, S.M. (Ed.) Molecular Recognition: Chemical and Biological Problems, Royal Society of London, London, (1989) pp. 182–196.Google Scholar
  13. 13.
    Pearlman, D.A. and Murcko, M.A., J. Comput. Chem., 14 (1993) 1184.Google Scholar
  14. 14.
    Böhm, H.J., J. Comput.-Aided Mol. Design, 6 (1992) 61.Google Scholar
  15. 15.
    Böhm H.J., J. Comput.-Aided Mol. Design, 6 (1992) 593.Google Scholar
  16. 16.
    Blaney, J.M. and Dixon, J.S., Perspect. Drug Discov. Design, 1 (1993) 301.Google Scholar
  17. 17.
    Kuntz, I.D., Meng, E.C. and Shoichet, B.K., Acc. Chem. Res., 27 (1994) 117.Google Scholar
  18. 18.
    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
  19. 19.
    Meng, E.C., Shoichet, B.K. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 505.Google Scholar
  20. 20.
    Meng, E.C., Gschwend, D.A., Blaney, J.M. and Kuntz, I.D., Proteins, 17 (1993) 266.Google Scholar
  21. 21.
    Kuntz, I.D., Science, 257 (1992) 1078.Google Scholar
  22. 22.
    Shoichet, B.K., Stroud, R.M., Santi, D.V., Kuntz, I.D. and Perry, K.M., Science, 259 (1993) 1445.Google Scholar
  23. 23.
    Lawrence, M.C. and Davis, P.C., Proteins, 12 (1992) 31.Google Scholar
  24. 24.
    Miller, M.D., Kearsley, S.K., Underwood, D.J. and Sheridan, R.P., J. Comput.-Aided Mol. Design, 8 (1994) 153.Google Scholar
  25. 25.
    Gehlhaar, D.K., Verkhivker, G.M., Rejto, P.A., Sherman, C.J., Fogel, D.B., Fogel, L.J. and Freer, S.T., Chem. Biol., 2 (1995) 317.Google Scholar
  26. 26.
    van Gunsteren, W.F. and Weiner, P.K., Computer Simulations of Biomolecular Systems, ESCOM, Leiden, 1989.Google Scholar
  27. 27. a.
    Kollman, P.A., Chem. Rev., 93 (1993) 2395.Google Scholar
  28. b.
    Kollman, P.A., Curr. Opin. Struct. Biol., 4 (1994) 240.Google Scholar
  29. 28.
    Warshel, A., Tao, H., Fothergill, M. and Chu, Z.T., Isr. J. Chem., 34 (1994) 253.Google Scholar
  30. 29.
    Honig, B. and Nicholls, A., Science, 268 (1995) 1144.Google Scholar
  31. 30.
    Grootenhuis, P.D.J. and Van Galen, P.J.M., Acta Crystallogr., D51 (1995) 560.Google Scholar
  32. 31.
    Kurinov, I.V. and Harrison, R.W., Nature Struct. Biol., 1 (1994) 735.Google Scholar
  33. 32.
    Holloway, M.K., Wai, J.M. and Halgren, T.A., J. Med. Chem., 38 (1995) 305.Google Scholar
  34. 33.
    Miranker A. and Karplus, M., Proteins Struct. Funct. Genet., 11 (1991) 29.Google Scholar
  35. 34.
    Vajda, S., Weng, Z., Rosenfeld, R. and DeLisi, C., Biochemistry, 33 (1994) 13977.Google Scholar
  36. 35.
    Krystek, S., Stouch, T. and Novotny, J., J. Mol. Biol., 234 (1993) 661.Google Scholar
  37. 36.
    Horton, N. and Lewis, M., Protein Sci., 1 (1992) 169.Google Scholar
  38. 37.
    Bohacek, R.S. and McMartin, C., J. Med. Chem., 35 (1992) 1671.Google Scholar
  39. 38.
    Jedrzejas, M.J., Singh, S., Brouillette, W.J., Air, G.M. and Luo, M., Proteins, 23 (1995) 264.Google Scholar
  40. 39.
    Nauchitel, V., Villaverde, M.C. and Sussman, F., Protein Sci., 4 (1995) 1356.Google Scholar
  41. 40.
    Peräkylä, M. and Pakkanen, T.A., Proteins, 20 (1994) 367.Google Scholar
  42. 41.
    Head, R.D., Smythe, M.L., Oprea, T.I., Waller, C.L., Green, S.M. and Marshall, G.R., J. Am. Chem. Soc., 118 (1996) 3959.Google Scholar
  43. 42.
    Jain, A.N., J. Comput.-Aided Mol. Design, 10 (1996) 427.Google Scholar
  44. 43.
    Böhm, H.J., J. Comput.-Aided Mol. Design, 8 (1994) 243.Google Scholar
  45. 44.
    Ajay and Murcko M.A., J. Med. Chem., 38 (1995) 4953.Google Scholar
  46. 45.
    Böhm, H.J., J. Comput.-Aided Mol. Design, 8 (1994) 623.Google Scholar
  47. 46.
    Mack, H., Pfeiffer, T., Hornberger, W., Böhm., H.J. and Höffken, H.W., J. Enzyme Inhibition, 9 (1995) 73.Google Scholar
  48. 47.
    Rarey, M., Wefing, S. and Lengauer, T., J. Comput.-Aided Mol. Design, 10 (1996) 41.Google Scholar
  49. 48.
    Burley, S.K. and Petsko, G.A., Science, 229 (1985) 23.Google Scholar
  50. 49.
    Hunter, C.A., Singh, J. and Thornton, J.M., J.Mol. Biol., 218 (1991) 837.Google Scholar
  51. 50.
    Hunter, C.A., Chem. Soc. Rev., (1994) 101.Google Scholar
  52. 51.
    Sander, C., personal communication.Google Scholar
  53. 52.
    GROMOS, user manual.Google Scholar
  54. 53.
    Jorgensen, W.L. and Pranata, J., J. Am. Chem. Soc., 112 (1990) 2008.Google Scholar
  55. 54.
    Connolly, M.L., Science, 221 (1983) 709.Google Scholar
  56. 55.
    Programs INSIGHT and DISCOVER, distributed by MSI, San Diego, CA.Google Scholar
  57. 56.
    Dauber-Osguthorpe, P., Roberts, V.A., Osguthorpe, D.J., Wolff, J., Genest, M. and Hagler, A.T., Proteins, 4 (1988) 31.Google Scholar
  58. 57.
    Kleywegt, G.J. and Jones, T.A., Acta Crystallogr., D50 (1994) 178.Google Scholar
  59. 58.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B, Meyer Jr., E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, T., J. Mol. Biol., 112 (1977) 535.Google Scholar
  60. 59.
    Wilson, D.K. and Quiocho, F.A., Biochem., 32 (1993) 1689.Google Scholar
  61. 60.
    Harvey, S.C., In Goodman, A. (Ed.) The Pharmacological Basics of Therapeutics, MacMillan Press, New York, NY (1987) pp. 980–985.Google Scholar
  62. 61.
    Mangani, S., Carloni, P. and Orioli, P., J. Mol. Biol., 223 (1992) 573.Google Scholar
  63. 62.
    Cappalonga, A.M., Alexander, R.S. and Christianson, D.W., J. Biol. Chem., 267 (1992) 19192.Google Scholar
  64. 63.
    Xiang, S., Short, S.A., Wolfenden, R. and Carter, C.W., Biochemistry, 34 (1995) 4516.Google Scholar
  65. 64.
    Mattos, C., Rasmussen, B., Ding, X., Petsko, G.A. and Ringe, D., Nature Struct. Biol., 1 (1994) 55.Google Scholar
  66. 65.
    Van Duyne, G.D., Standaert, R.F., Karplus, P.A., Schreiber, S.L. and Clardy, J., Science, 252 (1991) 839.Google Scholar
  67. 66.
    Kim, E.E., Baker, C.T., Dwyer, M.D., Murcko, M.A., Rao, B.G., Tung, R.D. and Navia, M.A., J. Am. Chem. Soc., 117 (1995) 1181.Google Scholar
  68. 67.
    Lam, P.Y.S., Jadhav, P.K., Eyermann, C.J., et al., Science, 263 (1994) 380.Google Scholar
  69. 68.
    Morton, A. and Matthews, B.W., Biochemistry, 34 (1995) 8576.Google Scholar
  70. 69.
    White, J.L., et al., J. Mol. Biol., 102 (1976) 759.Google Scholar
  71. 70.
    Bolognesi, M., Cannilo, E., Ascenzi, P., Giacometti, G.M., Merli, A. and Brunori, M., J. Mol. Biol., 158 (1982) 305.Google Scholar
  72. 71.
    Lipscomb, J.D., Biochemistry, 19 (1980) 3590.Google Scholar
  73. 72.
    Turk, D., Stürzebecher, J. and Bode, W., FEBS Lett., 287 (1991) 133.Google Scholar
  74. 73.
    Zollner, H., Handbook of Enzyme Inhibitors, VCH Publishers, Weinheim, 1993.Google Scholar
  75. 74.
    Cowan, S.W., Newcomer, M.E. and Jones, T.A., Proteins, 8 (1990) 44.Google Scholar
  76. 75.
    Wood, J., J. Cardiovasc. Pharm., 14 (1989) 221.Google Scholar
  77. 76.
    Jacobson, B.L., He, J.J., Vermersch, P.S., Lemon, D.D. and Quiocho, F.A., J. Biol. Chem., 266 (1991) 5220.Google Scholar
  78. 77.
    Weber, P.C., Wendoloski, J.J., Pantoliano, M.W. and Salemme, F.R., J. Am. Chem. Soc., 114 (1992) 3197.Google Scholar
  79. 78.
    Matthews, B.W., Acc. Chem. Res., 21 (1988) 333.Google Scholar
  80. 79.
    Fisher, M.T. and Sligar, S.G., J. Am. Chem. Soc., 107 (1985) 5018.Google Scholar
  81. 80.
    Teplyakov, A., Wilson, K.S., Orioli, P. and Mangani, S., Acta Crystallogr., D49 (1993) 534.Google Scholar
  82. 81.
    Cooper, J., Foundling, S., Hemmings, A. and Blundell, T., Eur. J. Biochem., 169 (1987) 215.Google Scholar
  83. 82.
    Miller, D.M., Olson, J.S., Pflugrath, J.W. and Quiocho, F.A., J. Biol. Chem., 258 (1983) 13665.Google Scholar
  84. 83.
    Watson, K.A., Mitchell, E.P., Johnson, L.N., Son, J.C., Bichard, C.J.F., Orchard, M.G., Fleet, G.W.J., Oikonomakos, N.G., Leonidas, D.D., Kontou, M. and Papageorgioui, A., Biochemistry, 33 (1994) 5745.Google Scholar
  85. 84.
    Lowe, J.B., Sacchettini, J.C., Laposata, M., McQuillan, J.J. and Gordon, J.I., J. Biol. Chem., 262 (1987) 5931.Google Scholar
  86. 85.
    Appelt, K., Bacquet, R.J., Bartlett, C.A., et al., J. Med. Chem., 34 (1991) 1925.Google Scholar
  87. 86.
    Bunting, J.W. and Myer, C.D., Can. J. Chem., 53 (1975) 1993.Google Scholar
  88. 87.
    Bolin, J.T., Filman, D.A., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.Google Scholar
  89. 88.
    Mares-Guia, M. and Shaw, E., J. Biol. Chem., 240 (1965) 1579.Google Scholar
  90. 89.
    Bode, W., J. Mol. Biol., 127 (1979) 357.Google Scholar
  91. 90.
    Wallace, R.A., Kurtz, A.N. and Niemann, C., Biochemistry, 2 (1963) 824.Google Scholar
  92. 91.
    Dani, M., Manca, F. and Rialdi, G., Biochim. Biophys. Acta, 667 (1981) 108.Google Scholar
  93. 92.
    Blaney, J.M., Hansch, C., Silipo, C. and Villon, A., Chem. Rev., 84 (1984) 333.Google Scholar
  94. 93.
    Blundell, T.L., Cooper, J., Foundling, S.I., Jones, D.M., Atrash, B. and Szelke, M., Biochemistry, 26 (1987) 5585.Google Scholar
  95. 94.
    Janes, W. and Schultz, G.E., J. Biol. Chem., 265 (1990) 10443.Google Scholar
  96. 95.
    Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B.H. and Wlodawer, S., Science, 246 (1989) 1149.Google Scholar
  97. 96.
    Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.Google Scholar
  98. 97.
    Welles, T.N.C. and Fersht, A.R., Biochemistry, 25 (1986) 1881.Google Scholar
  99. 98.
    Verlinde, C.L.M.J., Noble, M.E.M., Kalk, K.H., Groendijk, H., Wierenga, R.K. and Hol, W.G.J., Eur. J. Biochem., 198 (1991) 53.Google Scholar
  100. 99.
    Roderick, S.L., Fournie-Zuliski, M.C., Roques, B.P. and Matthews, B.W., Biochemistry, 28 (1989) 1493.Google Scholar
  101. 100.
    Schloss, J.V., Emptage, M.H. and Cleland, W.W., Biochemistry, 23 (1984) 4572.Google Scholar
  102. 101.
    Kim, H. and Lipscomb, W.N., Biochemistry, 29 (1990) 5546.Google Scholar
  103. 102.
    Lindquist, R.N., Lynn, J.L. and Lienhard, G.E., J. Am. Chem. Soc., 95 (1973) 8762.Google Scholar
  104. 103.
    Kim, H. and Lipscomb, W.N., Biochemistry, 30 (1991) 8171.Google Scholar
  105. 104.
    McPhalen, C.A., Vincent, M.G. and Jansonius, J.N., J. Mol. Biol., 225 (1992) 495.Google Scholar
  106. 105.
    Hol, W. and Verlinde, C., personal communication.Google Scholar
  107. 106.
    Bode, W., Turk, D. and Stürzebecher, J., Eur. J. Biochem., 193 (1990) 175.Google Scholar
  108. 107.
    Stürzebecher, J., Walsmann, P., Voigt, B. and Wagner, G., Thrombosis Res., 36 (1984) 457.Google Scholar
  109. 108.
    Hilpert, K., Ackermann, J., Banner, D.W., Gast, A., Gubernator, K., Hadvary, P., Labler, L., Müller, K., Schmid, G., Tschopp, T.B. and van de Waterbeemd, H., J. Med. Chem., 37 (1994) 3889.Google Scholar
  110. 109.
    Mitchell, E.P., Watson, K.A., Bichard, C., Fleet, G.W.J., Zographos, S.E., Oikonomakos, N.G., Board, M. and Johnson, L.N., In Hunter, W.N., Thornton, J.M. and Bailey, S. (Eds.) Making the Most of your Model, Proceedings of the CCP4 study weekend, Chester, 1995, pp. 111–119.Google Scholar
  111. 110.
    Brandstetter, H., Turk, D., Hoeffken, H.W., Grosse, D., Stürzebecher, J., Martin, P.D., Edwards, B.F.P. and Bode, W., J. Mol. Biol., 226 (1992) 1085.Google Scholar
  112. 111.
    Steinberg, G.M., Mednick, M.L., Maddox, J. and Rice, R., J. Med. Chem., 18 (1975) 1056.Google Scholar
  113. 112.
    Greer, J., Erickson, J.W., Baldwin, J.J. and Varney, M.D., J. Med. Chem., 37 (1994) 1035.Google Scholar
  114. 113.
    Markwardt, F., Walsmann, P. and Landmann, H., Pharmazie, 25 (1970) 551.Google Scholar
  115. 114.
    Kikumoto, R., Tamao, Y., Tezuka, T., Tonomura, S., Hara, H., Ninomiya, K., Hijikata, A. and Okamoto, S., Biochemistry, 23 (1984) 85.Google Scholar
  116. 115.
    Kim, K.H., Willingmann, P., Gong, Z.X., et al., J. Mol. Biol., 230 (1993) 206.Google Scholar
  117. 116.
    Entsch, B., Ballou, D.P. and Massey, V., J. Biol. Chem., 251 (1976) 2550.Google Scholar
  118. 117.
    Badger, J., Minor, I., Kremer, M.J., Oliveira, M.O., Smith, T.J., Griffith, J.P., Guerin, D.M.A., Krishnaswamy, S., Luo, M., Rossmann, M.G., McKinlay, M.A., Diana, G.D., Dutko, F.J., Fancher, M., Rueckert, R.R. and Heinz, B.A., Proc. Natl. Acad. Sci. USA, 85 (1988) 3304.Google Scholar
  119. 118.
    Herron, J.N., He, X., Mason, M.L., Voss, E.W. and Edmundson, A.B., Proteins, 5 (1989) 271.Google Scholar
  120. 119.
    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
  121. 120.
    Erickson, J., Neidhart, D.J., VanDrie, 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
  122. 121.
    Burkhard, P., Kallen, J., Mikol, V. and Walkinshaw, M.D., In Kungl, A.J., Andrew, P.J. and Schreiber, H. (Eds.) Proceedings of the ICSMB95, 1995, pp. 44–60.Google Scholar
  123. 122.
    Fersht, A.R., Shi, J.P., Knill-Jones, J., Lowe, D.M., Wilkinson, A.J., Blow, D.M., Brick, P., Carter, P., Waye, M.M.Y. and Winter, G., Nature, 314 (1985) 235.Google Scholar
  124. 123.
    Shirley, B.A., Stanssens, P., Hahn, U. and Pace, C.N., Biochemistry, 31 (1992) 725.Google Scholar
  125. 124.
    Connelly, P.R., Aldape, R.A., Bruzzese, F.J., Chambers, S.P., Fitzgibbon, M.J., Fleming, M.A., Itoh, S., Livingstone, D.J., Navia, M.A., Thomson, J.A. and Wilson, K.P., Proc. Natl. Acad. Sci. USA, 91 (1994) 1964.Google Scholar
  126. 125.
    Chen, Y.W., Fersht, A.R. and Henrick, K., J. Mol. Biol., 234 (1993) 1158.Google Scholar
  127. 126.
    Richards, F.M., Annu. Rev. Biophys. Bioeng., 6 (1977) 151.Google Scholar
  128. 127.
    Sharp, K.A., Nicholls, A., Friedman, R. and Honig, B., Biochemistry, 30 (1991) 9686.Google Scholar
  129. 128.
    Searle, M.S., Williams, D.H. and Gerhard, U., J. Am. Chem. Soc., 114 (1992) 10697.Google Scholar
  130. 129.
    Sali, A., Veerapandiam, B., Cooper, J.B., Moss, J.B., Hofmann, T. and Blundell, T.L., Proteins, 12 (1992) 158.Google Scholar
  131. 130.
    Wierenga, R.K., Noble, M.E.M. and Davenport, R.C., J.Mol. Biol., 224 (1992) 1115.Google Scholar
  132. 131.
    Dougherty, D.A. and Stauffer, D.A., Science, 250 (1990) 1558.Google Scholar
  133. 132.
    Baker, B.R. and Erickson, E.H., J. Med. Chem., 10 (1967) 1123.Google Scholar

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© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Hans-Joachim Böhm
    • 1
  1. 1.Central ResearchBASF AGLudwigshafenGermany

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