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Journal of Computer-Aided Molecular Design

, Volume 11, Issue 4, pp 333–344 | Cite as

QXP: Powerful, rapid computer algorithms for structure-based drug design

  • Colin Mcmartin
  • Regine S. Bohacek
Article

Abstract

New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An additional fast search step is introduced between the initial perturbation and energy minimization. The fast search produces approximate low-energy structures, which are likely to minimize to a low energy. For template fitting, QXP uses a superposition force field which automatically assigns short-range attractive forces to similar atoms in different molecules. The docking algorithms were evaluated using X-ray data for 12 protein–ligand complexes. The ligands had up to 24 rotatable bonds and ranged from highly polar to mostly nonpolar. Docking searches of the randomly disordered ligands gave rms differences between the lowest energy docked structure and the energy-minimized X-ray structure, of less than 0.76 Å for 10 of the ligands. For all the ligands, the rms difference between the energy-minimized X-ray structure and the closest docked structure was less than 0.4 Å, when parts of one of the molecules which are in the solvent were excluded from the rms calculation. Template fitting was tested using four ACE inhibitors. Three ACE templates have been previously published. A single run using QXP generated a series of templates which contained examples of each of the three. A pseudo-receptor, complementary to an ACE template, was built out of small molecules, such as pyrrole, cyclopentanone and propane. When individually energy minimized in the pseudo-receptor, each of the four ACE inhibitors moved with an rms of less than 0.25 Å. After random perturbation, the inhibitors were docked into the pseudo-receptor. Each lowest energy docked structure matched the energy-minimized geometry with an rms of less than 0.08 Å. Thus, the pseudo-receptor shows steric and chemical complementarity to all four molecules. The QXP program is reliable, easy to use and sufficiently rapid for routine application in structure-based drug design.

Structure-based design Pharmacophore Docking Pseudo-receptor Force field Metropolis Simulated annealing Monte Carlo search Conformational analysis 

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References

  1. 1.
    Erickson, J.W. and Fesik, S.W., In Venuti, M.C. (Ed.) Annual Reports of Medicinal Chemistry, Academic Press, New York, NY, U.S.A., 1992, p. 271.Google Scholar
  2. 2.
    Greer, J., Erickson, J.W., Baldwin, J.J. and Varney, J., J. Med. Chem., 37 (1994) 1035.Google Scholar
  3. 3.
    Bohacek, R.S., McMartin, C. and Guida, W.C., Rev. Med. Chem., in press.Google Scholar
  4. 4.
    Kearsley, S.K. and Smith, G.M., Tetrahedron Comput. Methodol., 3 (1990) 615.Google Scholar
  5. 5.
    Klebe, G., Mietzner, T. and Weber, F., J. Comput.-Aided Mol. Design, 8 (1994) 751.Google Scholar
  6. 6.
    McMartin, C. and Bohacek, R.S., J. Comput.-Aided Mol. Design, 9 (1995) 237.Google Scholar
  7. 7.
    Guida, W.C., Bohacek, R.S. and Erion, M.D., J. Comput. Chem., 13 (1992) 214.Google Scholar
  8. 8.
    Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Ghio, C., Algona, G., Profeta, S. and Weiner, P., J. Am. Chem. Soc., 106 (1984) 765.Google Scholar
  9. 9.
    Mohamadi, F., Richards, N.G., Guida, W.C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Hendrikson, T. and Still, C., J. Comput. Chem., 11 (1990) 440.Google Scholar
  10. 10.
    Polak, E. and Ribiere, G., Revue Française Inf. Rech. Oper., 16-R1 (1969) 35.Google Scholar
  11. 11.
    Beeman, D., J. Chem., 20 (1976) 130.Google Scholar
  12. 12.
    Metropolis, N., Rosenbluth, A., Rosaenbluth, M., Teller, A. and Teller, E., J. Chem. Phys., 21 (1953) 1087.Google Scholar
  13. 13.
    Abol, E.E., Bernstein, F.C., Bryant, S.H., Koetzle, T.F. and Weng, J., In Allen, F.H., Bergerhoff, G. and Sievers, R. (Eds.) Crystallographic Data-bases - Information Content, Software Systems, Scientific Applications, Data Commission of the International Union of Crystallography, Bonn/Cambridge/Chester, 1987, pp. 107–132.Google Scholar
  14. 14.
    Roderick, S.L., Fournie-Zaluski, M.C., Roques, B.P. and Matthews, B.W., Biochemistry, 28 (1989) 1493.Google Scholar
  15. 15.
    Monzingo, A.F. and Matthews, B.W., Biochemistry, 21 (1982) 3390.Google Scholar
  16. 16.
    Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.Google Scholar
  17. 17.
    Hosur, M.V., Bhat, T.N., Kemp, D., Baldwin, E.T., Liu, B., Gulnik, S., Wideburg, N.E., Norbeck, D.W., Appelt, K. and Erickson, J.W., J. Am. Chem. Soc., 116 (1994) 847.Google Scholar
  18. 18.
    Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.Google Scholar
  19. 19.
    Kim, H. and Lipscomb, W.N., Biochemistry, 30 (1991) 8171.Google Scholar
  20. 20.
    Cheetam, J.C., Artymuik, P.J. and Phillips, D.C., J. Mol. Biol., 224 (1993) 613.Google Scholar
  21. 21.
    Wilson, D.K., Rudolph, F.B. and Quicho, F.A., Science, 252 (1991) 1278.Google Scholar
  22. 22.
    Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S.R. and Hofsteenge, J., EMBO J., 8 (1989) 3467.Google Scholar
  23. 23.
    Cowan, S.W., Newcomer, M.E. and Jones, T.A., Proteins, 8 (1990) 44.Google Scholar
  24. 24.
    Spurlino, J.C., Smallwood, A.M., Carlton, D.D., Banks, T.M., Vavra, K.J., Johnson, J.S., Cook, E.R., Falvo, G.J., Wahl, R.C. and Pulvino, T.A., Proteins, 19 (1994) 98.Google Scholar
  25. 25.
    Weber, P.C., Ohlendorf, D.H., Wendoloski, J.J. and Salemme, F.R., Science, 85 (1989) 243.Google Scholar
  26. 26.
    Teeter, M.M., Proc. Natl. Acad. Sci. USA, 81 (1984) 6104.Google Scholar
  27. 27.
    Sacchettini, J.C., Gordon, J.I. and Banszak, L.J., J. Mol. Biol., 208 (1989) 327.Google Scholar
  28. 28.
    Wlodawer, A., Walter, J., Huber, L. and Sjolin, L., J. Mol. Biol., 180 (1984) 301.Google Scholar
  29. 29.
    Whitlow, M. and Teeter, M.M., J. Am. Chem. Soc., 108 (1986) 7163.Google Scholar
  30. 30.
    Cushman, D.W., Cheung, H.S., Sabo, E.F. and Ondetti, M.A., Biochemistry, 16 (1977) 5484.Google Scholar
  31. 31.
    Hassall, C.H., Kroehn, A., Moody, C.J. and Thomas, W.A., J. Chem. Soc. Perkin Trans. I, (1984) 155.Google Scholar
  32. 32.
    Weller, H.N., Gordon, E.M., Rom, M.B. and Plusces, J., Biochem. Biophys. Res. Commun., 125 (1984) 82.Google Scholar
  33. 33.
    Watthey, J.W.H., Stanton, J.L., Desai, M., Babiarz, J.E. and Finn, B.M., J. Med. Chem., 28 (1985) 1511. ACE activity was measured with the substrate hippuryl-His-Leu using the procedure described by Cushman, D.W. and Cheung, H.W., Biochem. Pharmacol., 20 (1971) 1637.Google Scholar
  34. 34.
    Andrews, P.R., Carson, J.M., Caselli, A., Spark, M.J. and Woods, R., J. Med. Chem., 28 (1985) 393.Google Scholar
  35. 35.
    Mayer, D., Naylor, C.B., Motoc, I. and Marshall, G.R., J. Comput.-Aided Mol. Design, 1 (1987) 3.Google Scholar
  36. 36.
    Hausin, R.J. and Codding, P.W., J. Med. Chem., 33 (1990) 1940.Google Scholar
  37. 37.
    MacroModel v. 2.5 was obtained from Professor W. Clark Still, Columbia University, New York, NY, U.S.A.Google Scholar
  38. 38.
    Bohacek, R.S.B. and McMartin, C., J. Am. Chem. Soc., 116 (1994) 5560.Google Scholar
  39. 39.
    Bohacek, R.S., De Lombaert, S., McMartin, C., Priestle, J. and Gruetter, M., J. Am. Chem. Soc., 118 (1996) 8231.Google Scholar
  40. 40.
    Meng, E.C., Shoichet, B.K. and Kuntz, I.D., J. Comput. Chem., 13 (1992) 505.Google Scholar
  41. 41.
    Goodsell, D.S. and Olsen, A.J., Proteins Struct. Funct. Genet., 8 (1990) 195.Google Scholar
  42. 42.
    Sobolev, V., Wade, R.C., Vriend, G. and Edelman, M., Proteins, 25 (1996) 120.Google Scholar
  43. 43.
    Mitzutani, M.Y., Tomioka, N. and Itai, A., J. Mol. Biol., 235 (1994) 318.Google Scholar
  44. 44.
    Hart, T.N. and Read, R.J., Proteins, 13 (1992) 206.Google Scholar
  45. 45.
    Welch, W., Ruppert, J. and Jain, A.N., Chem. Biol., 3 (1996) 449.Google Scholar
  46. 46.
    Kuntz, I.D., Meng, E.C. and Shoichet, B.K., Acc. Chem. Res., 27 (1994) 117.Google Scholar
  47. 47.
    Ksander, G.M., De Jesus, R., Yuan, A., Ghai, R.D., Trapani, A., McMartin, C. and Bohacek, R., J. Med. Chem., 40 (1997) 495.Google Scholar
  48. 48.
    Ksander, G.M., De Jesus, R., Yuan, A., Ghai, R.D., McMartin, C. and Bohacek, R., J. Med. Chem., 40 (1997) 506.Google Scholar
  49. 49.
    FLO96, Morristownship, NJ, U.S.A., tel.: 201 455 1229, e-mail: cmcma @ix.netcom.com.Google Scholar
  50. 50.
    Bohacek, R.S. and McMartin, C., J. Med. Chem., 35 (1992) 1671.Google Scholar

Copyright information

© Kluwer Academic Publishers 1997

Authors and Affiliations

  • Colin Mcmartin
    • 1
  • Regine S. Bohacek
    • 1
  1. 1.Research DepartmentNovartis Pharmaceuticals CorporationSummitU.S.A.

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