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Docking and scoring of metallo-β-lactamases inhibitors

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Abstract

The performance of the AutoDock, GOLD and FlexX docking programs was evaluated for docking of dicarboxylic acid inhibitors into metallo-β-lactamases (MBLs). GOLD provided the best overall performance, with RMSDs between experimental and docked structures of 1.8–2.6 Å and a good correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores. GOLD was selected for a test including a broad spectrum of inhibitors for which experimental MBL-inhibitor binding affinities are available. This study revealed that (1) for most compound classes (dicarboxylic acids, tetrazoles, sulfonylhydrazones, and peptide-like compounds) there is a good correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores, (2) the correlation only holds within a given class, that is, scores of compounds from different classes cannot be directly compared, (3) for some compound classes (e.g. small sulphur compounds) there is no direct correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores. Using partial least squares methods, a model with R2=0.82 and Q2=0.78 for the training set was obtained based on the GOLD score and descriptors associated with binding of the IMP-1 inhibitors to the enzyme. The external Q2 for the test set is 0.73. This final model for prediction of IMP-1 MBL-inhibitor affinity handled all known classes of MBL-inhibitors, except small sulphur compounds.

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References

  1. Medeiros, A.A., Clin. Infect. Diseases, 24 (1997) 19.

    Google Scholar 

  2. Matagne, A., Dubus, A., Galleni, M. and Frere, J.-M., Nat. Prod. Rep., 16 (1999) 1.

    Google Scholar 

  3. Ambler, R.P., Philos. Trans. R. Soc. London, 289 (1980) 321.

    Google Scholar 

  4. Cornaglia, G., Riccio, M.L., Mazzariol, A., Lauretti, L., Fontana, R. and Rossolini, G.M., Lancet, 353 (1999) 899.

    Google Scholar 

  5. Livermore, D.M. and Woodford, N., Curr. Opin. Microbiol., 3 (2000) 489.

    Google Scholar 

  6. Galleni, M., Lamotte-Brasseur, J., Rossolini, G.M., Spen-cer, J., Dideberg, O. and Frère, J.-M., Antimicrob. Agents Chemother., 45 (2001) 660.

    Google Scholar 

  7. Toney, J.H., Hammond, G.G., Fitzgerald, P.M.D., Sharma, N., Balkovec, J.M., Rouen, G.P., Olson, S.H., Hammond, M.L., Greenlee, M.L. and Gao, Y.-D., J. Biol. Chem., 276 (2001) 31913.

    Google Scholar 

  8. Concha, N.O., Janson, C.A., Rowling, P., Pearson, S., Cheever, C.A., Clarke, B.P., Lewis, C., Galleni, M., Frère, J.-M., Payne, D.J., Bateson, J.H. and Abdel-Meguid, S.S., Biochemistry, 39 (2000) 4288.

    Google Scholar 

  9. Concha, N.O., Rasmussen, B.A., Bush, K. and Herzberg, O., Structure, 4 (1996) 823.

    Google Scholar 

  10. Concha, N.O., Rasmussen, B.A., Bush, K. and Herzberg, O., Protein Sci., 6 (1997) 2671.

    Google Scholar 

  11. Fitzgerald, P.M.D., Wu, J.K. and Toney, J.H., Biochemistry, 37 (1998) 6791.

    Google Scholar 

  12. Toney, J.H., Fitzgerald, P.M.D., Grover-Sharma. N., Olson, S.H., May, W.J., Sundelof, J.G., Vanderwall, D.E., Cleary, K.A., Grant, S.K., Wu, J.K., Kozarich, J.W., Pompliano, D.L. and Hammond, G.G., Chem. Biol., 5 (1998) 185.

    Google Scholar 

  13. Carfi, A., Pares, S., Duée, E., Galleni, M., Duez, C., Frére, J.-F. and Dideberg, O., EMBO J., 14 (1995) 4914.

    Google Scholar 

  14. Carfi, A., Duée, E., Paul-Soto, R., Galleni, M., Frère, J.-M. and Dideberg, O. Acta Crystallogr., D54 (1998) 47.

    Google Scholar 

  15. Fabiane, S.M., Sohi, M.K., Wan, T., Payne, D.J., Bateson, J.H., Mitchell, T. and Sutton, B.J., Biochemistry, 37 (1998) 12404.

    Google Scholar 

  16. Ullah, J.H., Walsh, T.R., Taylor, I.A., Emery, D.C., Verma, C.S., Gamblin, S.J. and Spencer, J., J. Mol. Biol., 284 (1998) 125.

    Google Scholar 

  17. Garzía, I., Mercuri, P.S., Papamicael, C., Kahn, R., Frére, J.-M., Galleni, M., Rossolini, G.M. and Dideberg, O., J. Mol. Biol., 325 (2003) 651.

    Google Scholar 

  18. Walter, M.W., Felici, A., Galleni, M., Paul-Soto, R., Adling-ton, R.M., Baldwin, J.E., Frére, J.-M., Gololobov, M. and Schofield, C.J., Bioorg. Med. Chem. Lett., 6 (1996) 2455.

    Google Scholar 

  19. Nagano, R., Adachi, Y., Imamura, H., Yamada, K., Hashi-zume, T. and Morishima, H., Antimicrob. Agents Chemother., 43 (1999) 2497.

    Google Scholar 

  20. Zervosen, A., Valladares, M.H., Devreese, B., Prosperi-Meys, C., Adolph, H.-W., Mercuri, P.S., Vanhove, M., Amicosante, G., Beeumen, J.v. and Frère, J.-M., Eur. J. Biochem., 268 (2001) 3840.

    Google Scholar 

  21. Walter, M.W., Valladares, M.H., Adllington, R.M., Ami-cosante, G., Baldwin, J.E., Frère, J.-M., Galleni, M., Ros-solini, G.M. and Schoefield, C.J., Bioorg. Chem., 27 (1999) 35.

    Google Scholar 

  22. Yang, K.W. and Crowder, M.W., Arch. Biochem. Biophys., 368 (1999) 1.

    Google Scholar 

  23. Bounaga, S., Galleni, M., Laws, A.P. and Page, M.I., Bioorg. Med. Chem., 9 (2001) 503.

    Google Scholar 

  24. Mollard, C., Moali, C., Papamicael, C., Damblon, C., Vessilier, S., Amicosante, G., Schofield, C.J., Galleni, M., Frère, J.-M. and Roberts, G.C.K., J. Biol. Chem., 276 (2001) 45015.

    Google Scholar 

  25. Siemann, S., Clarke, A.J., Viswanatha, T. and Dmitrienko, G.I., Biochemistry, 42 (2003) 1673.

    Google Scholar 

  26. Payne, D.J., Bateson, J.H., Gasson, B.C., Proctor, D., Khushi, T., Farmer, T.H., Tolson, D.A., Bell, D., Skett, P.W., Mar-shall, C., Reid, R., Ghosez, L., Combret, Y. and Marchand-Brynaert, J., Antimicrob. Agents Chemother., 41 (1997) 135.

    Google Scholar 

  27. Heinz, U., Wommer, S., Meyer-Klaucke, W., Bauer, R., Papamicael, C., Bateson, J. and Adolph., H.-W., J. Biol. Chem., 278 (2003) 20659.

    Google Scholar 

  28. Payne, D.J., Hueso-Rodríguez, J.A., Boyd, H., Concha, N.O., Janson, C.A., Gilpin, M., Bateson, J.H., Cheever, C., Nicon-ovich, N.L., Pearson, S., Rittenhouse, S., Tew, D., Díez, E., Pérez, P., de la Fuente, J., Rees, M. and Rivera-Sagredo, A., Antimicrob. Agents Chemother., 46 (2002) 1880.

    Google Scholar 

  29. Siemann, S., Evanoff, D.P., Marrone, L., Clarke, A.J., Viswanatha, T. and Dmitrienko, G.I., Antimicrob. Agents Chemother., 46 (2002) 2450.

    Google Scholar 

  30. Gubernator, K. and Böhm, H.-J. (eds.) Structure-Based Lig-and Design, Wiley-VCH, Weinheim, Germany, 1998 and references therein.

  31. Swanstrom, R. and Erona, J., Pharmacol. Therapeut., 86 (2000) 145.

    Google Scholar 

  32. Schneider, G. and Böhm, H.-J., Drug Discov. Today, 7 (2002) 64.

    Google Scholar 

  33. Böhm, H.-J. and Stahl, M., Rev. Comput. Chem., 18 (2002) 41.

    Google Scholar 

  34. Carlson, H.A., Curr. Opin. Chem. Biol., 6 (2002) 447.

    Google Scholar 

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

    Google Scholar 

  36. Claußen, H., Buning, C., Rarey, M. and Lengauer, T., J. Mol. Biol., 308 (2001) 377.

    Google Scholar 

  37. Hoffmann, D., Kramer, B., Washio, T., Steinmetzer, T., Rarey, M. and Lengauer, T., J. Med. Chem. 42, (1999) 4422.

    Google Scholar 

  38. Charifson, P.S., Corkery, J.J., Murcko, M.A. and Walters, W.P., J. Med. Chem., 42 (1999) 5100.

    Google Scholar 

  39. Terp, G.E., Johansen, B.N., Christensen, I.T. and Jørgensen, F.S., J. Med. Chem., 44 (2001) 2333.

    Google Scholar 

  40. Stahl, M. and Rarey, M., J. Med. Chem., 44 (2001) 1035.

    Google Scholar 

  41. Stahl, M. and Böhm, H.-J., J. Mol. Graph. Mod., 16 (1998) 121.

    Google Scholar 

  42. Sybyl, Tripos Associates Inc., St. Louis, MO, USA.

  43. Halgren, T.A., J. Comput. Chem., 17 (1996) 490.

    Google Scholar 

  44. Halgren, T.A., J. Comput. Chem., 17 (1996) 520.

    Google Scholar 

  45. Halgren, T.A., J. Comput. Chem., 17 (1996) 553.

    Google Scholar 

  46. Halgren, T.A., J. Comput. Chem., 17 (1996) 616.

    Google Scholar 

  47. Halgren, T.A. and Nachbar, R.B., J. Comput. Chem., 17 (1996) 587.

    Google Scholar 

  48. Halgren, T.A., J. Comput. Chem., 20 (1999) 720.

    Google Scholar 

  49. Halgren, T.A., J. Comput. Chem., 20 (1999) 730.

    Google Scholar 

  50. Damblon, C., Jensen, M., Papamicael, C., Barsukov, I., Ab-abou, A., Schofield, C.J., Olsen, L., Bauer, R. and Roberts, G.C.K., J. Biol. Chem., 278 (2003) 29240.

    Google Scholar 

  51. Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K. and Olson, A.J., J. Comput. Chem., 19 (1998) 2639.

    Google Scholar 

  52. Hanessian, S., Moitessier, N. and Therrien, E., J. Comput.-Aided Mol. Design, 15 (2001) 873.

    Google Scholar 

  53. Hoops, S.C., Anderson, K.W. and Merz, K.M., J. Am. Chem. Soc., 113 (1991) 8262.

    Google Scholar 

  54. Dewar M.J.S. and Thiel W., J. Am. Chem. Soc., 99 (1977) 4899.

    Google Scholar 

  55. Dewar M.J.S. and Thiel W., J. Am. Chem. Soc., 99 (1977) 4907.

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  59. Kramer, B., Rarey, M. and Lengauer, T., Proteins, 37 (1999) 228.

    Google Scholar 

  60. Goodford, P. J., J. Med. Chem., 28 (1985) 849.

    Google Scholar 

  61. Boobbyer, D.N.A., Goodford, P.J., McWhinnie, P.M. and Wade, R.C., J. Med. Chem., 32 (1989) 1083.

    Google Scholar 

  62. Wade, R.C., Clark, K.J. and Goodford, P.J., J. Med. Chem., 36 (1993) 140.

    Google Scholar 

  63. Wade, R.C. and Goodford, P.J., J. Med. Chem., 36 (1993) 148.

    Google Scholar 

  64. GRID manual, Chapter 36, cf. http://www.mol-discovery. com/docs/grid21.

  65. Barone, V. and Cossi, M., J. Phys. Chem., 102 (1998) 1995.

    Google Scholar 

  66. Rega, N., Cossi, M. and Barone, V., J. Comput. Chem., 20 (1999) 1186.

    Google Scholar 

  67. Lee, C., Yang, W. and Parr, R.G., Phys. Rev. B, 37 (1988) 758.

    Google Scholar 

  68. Becke, A.D., J. Chem. Phys., 98 (1993) 1372.

    Google Scholar 

  69. Becke, A.D., J. Chem. Phys., 98 (1993) 5648.

    Google Scholar 

  70. Hehre, W.J., Ditchfield, R. and Pople, J.A., J. Chem. Phys., 56 (1972) 2257.

    Google Scholar 

  71. Ditchfield, R., Hehre, W.J. and Pople, J.A., J. Chem. Phys., 54 (1971) 724.

    Google Scholar 

  72. Hariharan, P.C. and Pople, J.A., Mol. Phys., 27 (1974) 209.

    Google Scholar 

  73. Gordon, M.S., Chem. Phys. Lett., 76 (1980) 163.

    Google Scholar 

  74. Hariharan, P.C. and Pople, J.A., Theor. Chim. Acta, 28 (1973) 213.

    Google Scholar 

  75. Stewart, J.J.P., J. Comput. Chem., 10 (1989) 209.

    Google Scholar 

  76. Stewart, J.J.P., J. Comput. Chem., 10 (1989) 221.

    Google Scholar 

  77. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Mont-gomery, J.A., Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Menucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochter-ski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Malick, D.K., Rabuck A.D., Ragavachari, K., Fores-man, J.B., Cioslowski, J., Ortiz, J.V., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B.G., Chen, W., Wong, M.W., Andres, J.L., Head-Gordon, M., Replogle, E.S. and Pople, J.A., Gaussian, Inc., Pittsburg, PA, 1998.

  78. Simca-P, Umetrics-AB, Umeå, Sweden.

  79. Eriksson, L., Johansson, E., Kettaneh-Wold, N. and Wold, S., Multi-and Megavariate Data Analysis. Principles and Applications, Umetrics-AB, Umeå, Sweden, 2001.

  80. Powell, J.W. and Whiting, M.C., Tetrahedron, 7 (1959) 305.

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Lars Olsen

  2. Protein Structure, Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark

    Ingrid Pettersson & Lars Hemmingsen

  3. Center for Bioinformatics, University of the Saarland and Max-Planck-Institut for Informatics, D-66041, Saarbrücken, Germany

    Hans-Werner Adolph

  4. Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Flemming Steen Jørgensen

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Olsen, L., Pettersson, I., Hemmingsen, L. et al. Docking and scoring of metallo-β-lactamases inhibitors. J Comput Aided Mol Des 18, 287–302 (2004). https://doi.org/10.1023/B:JCAM.0000046821.15502.71

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