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Journal of Computer-Aided Molecular Design

, Volume 13, Issue 1, pp 35–49 | Cite as

Methodological developments and strategies for a fast flexible superposition of drug-size molecules

  • Gerhard Klebe
  • Thomas Mietzner
  • Frank Weber
Article

Abstract

An alternative to experimental high through-put screening is the virtual screening of compound libraries on the computer. In absence of a detailed structure of the receptor protein, candidate molecules are compared with a known reference by mutually superimposing their skeletons and scoring their similarity. Since molecular shape highly depends on the adopted conformation, an efficient conformational screening is performed using a knowledge-based approach. A comprehensive torsion library has been compiled from crystal data stored in the Cambridge Structural Database. For molecular comparison a strategy is followed considering shape associated physicochemical properties in space such as steric occupancy, electrostatics, lipophilicity and potential hydrogen-bonding. Molecular shape is approximated by a set of Gaussian functions not necessarily located at the atomic positions. The superposition is performed in two steps: first by a global alignment search operating on multiple rigid conformations and then by conformationally relaxing the best scored hits of the global search. A normalized similarity scoring is used to allow for a comparison of molecules with rather different shape and size. The approach has been implemented on a cluster of parallel processors. As a case study, the search for ligands binding to the dopamine receptor is given.

knowledge-based conformational search molecular similarity molecular superposition torsional library virtual screening 

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References

  1. 1.
    Brandt, D.W., Drug Discov. Today, 3 (1998) 61.Google Scholar
  2. 2.
    Blaney, J.M. and Dixon, J.S., Perspect. Drug Discov. Design, 1 (1993) 301; Colman, P.M., Curr. Opin. Struct. Biol., 4 (1994) 868; Kuntz, I.D., Science, 257 (1992) 1078; Lengauer, T. and Rarey, M., Curr. Opin. Struct. Biol., 6 (1996) 402; Lybrand, T.P., Curr. Opin. Struct. Biol., 5 (1995) 224.Google Scholar
  3. 3.
    Downs, G.M. and Willet, P., In 'Reviews in Computational Chemistry' Vol. 7, pp. 1–66, Lipkowitz, K. and Boyd, D. (Eds), VCH; Good, A.C. and Mason, J.S., In 'Reviews in Computational Chemistry' Vol. 7, pp. 67–118, Lipkowitz, K. and Boyd, D. (Eds), VCH; Bures, M.G., Practical Application of Computer-Aided Drug Design, pp. 39–72, Marcel Dekker, New York, NY, USA (1997).Google Scholar
  4. 4.
    Hahn, M., J. Chem. Inf. Comput. Sci., 37 (1997) 80; Perry, N.C. and v. Geerestein, V.J., J. Chem. Inf. Comput. Sci., 32 (1992) 607; Parretti, M.F., Kroemer, R.T., Rothmann, J.H. and Richards, W.G., J. Comput. Chem., 18 (1997) 1344; Mc-Martin, C. and Bohacek, R.S., J. Comput.-Aided Mol. Design, 9 (1995) 237; Kato, Y., Inoue, A., Yamada, M., Tomioka, N. and Itai, A., J. Comput.-Aided Mol. Design, 6 (1992) 475.Google Scholar
  5. 5.
    Perkins, T.D.J., Mills, J.E.J. and Dean, P.M., J. Comput.-Aided Mol. Design, 9 (1995) 479; Hurst, T., J. Chem. Inf. Comput. Sci., 34 (1994) 190; Thorner, D.A., Wild, D.J., Willett, P. and Wright, P.M., J. Chem. Inf. Comput. Sci., 36 (1996) 900; Jones, G., Willett, P. and Glen, R.C., J. Comput.-Aided Mol. Design, 9 (1995) 532.Google Scholar
  6. 6.
    Klebe, G. and Mietzner, T., J. Comput.-Aided Mol. Design, 8 (1994) 583.Google Scholar
  7. 7.
    Allen, F.H. and Kennard, O., Acc. Chem. Res., 16 (1983) 146.Google Scholar
  8. 8.
    Klebe, G., in 'Structure Correlation', Eds. Bürgi, H.B. and Dunitz, J.D., VCH (1994) p. 543.Google Scholar
  9. 9.
    DeClerq, P.J., Hoflack, J. and Cauwbergh, S., QCPE Program No. QCMP079.Google Scholar
  10. 10.
    Sadowski, J., Rudolph, C. and Gasteiger, J., Tetrahedron Comput. Methodol., 3 (1990) 537.Google Scholar
  11. 11.
    Program SYBYL from Tripos Ass., Inc, St. Louis, MO, USA.Google Scholar
  12. 12.
    The authors are grateful to Dr. G. Vriend (EMBL, Heidelberg, Germany) for providing the data of tripeptide fragments.Google Scholar
  13. 13.
    Vriend, G., J. Mol. Graph., 8 (1990) 52.Google Scholar
  14. 14.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rogers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.Google Scholar
  15. 15.
    The following small molecule ligands have been used (labeled by their Refcodes in the PDB):1cbx, 1dhf, 1dwc, 1dwd, 1dwe, 1eed, 1ent, 1gpy, 1hiv, 1hos, 1ivp, 1ivq, 1pph, 1stp, 1thl, 1tlp, 1tmn, 1tpp, 2er7, 2hat, 2mip, 2r04, 2r06, 2r07, 2rm2, 2rr1, 2rs1, 2rs3, 2rs5, 2tmn, 3cpa, 3gpb, 3tmn, 4dfr, 4er1, 4er2, 4gpb, 4hvp, 4phv, 4tapap, 4tln, 4tmn, 5er1, 5er2, 5gpb, 5hvp, 5tln, 5tmn, 6cpa, 7cpa, 7hvp, 8cpa, 8hvp, 9hvp, lysozyme: α-, β-N-acetylglucosamide, thermolysin: β-ppp, cbzphe, thiorphan, retro-thiorphan.Google Scholar
  16. 16.
    Clark, M., Cramer, III, R.D. and v. Opdenbosch, N., J. Comput. Chem., 10 (1989) 982.Google Scholar
  17. 17.
    The following subset of ligands from [15] has been used: 1cbx, 1dhf, 1dwd, 1dwe, 1gpy, 1pph,1stp, 1thl, 1tlp, 1tmn, 2tmn, 3cpa, 3gpb, 3tmn, 4dfr, 4tln, 4tmn, 4-tapap, 5gpb, 5tln, 5tmn, 6cpa, 7cpa, 8cpa, β-ppp, cbzphe, thiorphan, retro-thiorphan.Google Scholar
  18. 18.
    Klebe, G., Perspect. Drug Discov. Design, 3 (1995) 85.Google Scholar
  19. 19.
    Kearsley, S.K. and Smith, G.M., Tetrahed. Comput. Meth., 3 (1990) 615.Google Scholar
  20. 20.
    Dewar, M.J.S., Zoebisch, E.G., Healy, E.F. and Stewart, J.J.P., J. Am. Chem. Soc., 107 (1985) 3902.Google Scholar
  21. 21.
    Viswanadhan, V.N., Ghose, A.K., Revankar, G.R. and Robins, R.K., J. Chem. Inf. Comput. Sci., 29 (1989) 163.Google Scholar
  22. 22.
    Klebe, G., Mietzner, T. and Weber, F., J. Comput.-Aided Mol. Design, 8 (1994) 751.Google Scholar
  23. 23.
    Martin, Y.C., Bures, M.G., Danaher, E.A., DeLazzer, J., Lico, I. and Pavlik, P., J. Comput.-Aided Mol. Design, 7 (1993) 83.Google Scholar
  24. 24.
    Klebe, G., J. Mol. Biol., 237 (1994) 212.Google Scholar
  25. 25.
    Bruno, I.J., Cole, J.C., Lommerse, J.P.M., Rowland, R.S., Taylor, R. and Verdonk, M.L., J. Comput.-Aided Mol. Design, 11 (1997) 525.Google Scholar
  26. 26.
    Böhm, H.J., Brode, S., Hesse, U. and Klebe, G., Chem. Eur. J., 2 (1996) 1509.Google Scholar
  27. 27.
    Good, A.C. and Richards, W.G., J. Chem. Inf. Comput. Sci., 33 (1993) 112.Google Scholar
  28. 28.
    Mestres, J., Rohrer, D.C. and Maggiora, G.M., J. Comput. Chem., 18 (1997) 934; Mestres, J., Rohrer, D.C. and Maggiora, G.M., J. Mol. Graphics, 15 (1997) 114; Leherte, L., Latour, T. and Vercauteren, D., J. Comput.-Aided Mol. Design, 10 (1996) 55; Grant, J.A., Gallardo, M.A. and Pickup, B.T., J. Comput. Chem., 17 (1996) 1653; Lemmen, C. and Lengauer, T., J. Comput.-Aided Mol. Design, 11 (1997) 357; Lemmen, C., Hiller, C. and Lengauer, T., J. Comput.-Aided Mol. Design, 12 (1998) 491; Nissink, J.W.M., Verdonk, M.L., Kroon, J., Mietzner, T. and Klebe, G., J. Comput. Chem., 18 (1997) 638.Google Scholar
  29. 29.
    Badger, J., Minor, I., Kremer, M.J., Oliveira, M.A., Smith, T.J., Griffith, J.P., Guerin, D.M.A., Krishaswamy, 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
  30. 30.
    Klebe, G., In Kubinyi, H. (Ed.), 3D QSAR in Drug Design, ESCOM, Leiden, 1993, pp. 173–199.Google Scholar
  31. 31.
    Gerber, P.R. and Müller, K., J. Comput.-Aided Mol. Design, 9 (1995) 251.Google Scholar
  32. 32.
    Ujvary, I., BIOSTER, available through Synopsys Scientific Systems Ltd., 175 Woodhouse Lane, Leeds, UK.Google Scholar
  33. 33.
    The Available Chemicals Directory is distributed through Molecular Design Ltd., San Leandros, CA (USA).Google Scholar
  34. 34.
    World Drug Index; Version 2/96, Derwent Information, 1996.Google Scholar
  35. 35.
    MPI: A Message Passing Interface Standard, Message Passing Interface Forum, April 15, 1994, Univ. of Tennessee, Knoxville, TN, USA.Google Scholar
  36. 36.
    Böhm, H.J. and Klebe, G., Angew. Chem., Int. Ed. Engl., 35 (1996) 2588.Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Gerhard Klebe
    • 1
  • Thomas Mietzner
    • 1
  • Frank Weber
    • 1
  1. 1.BASF AG, HauptlaboratoriumLudwigshafenGermany

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