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Computer-aided drug design: A free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase

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Summary

Molecular dynamics simulation and free energy perturbation techniques have been used to study the relative binding free energies of 8-methylpterins and 8-methyl-N5-deazapterins to dihydrofolate reductase (DHFR). Methyl-substitution at the 5, 6 and 7 positions in the N-heterocyclic ring gives rise to a variety of ring substituent patterns and biological activity: several of these methyl derivatives of the 8-methyl parent compounds (8-methylpterin and 8-methyl-N5-deazapterin) have been identified as substrates or inhibitors of vertebrate DHFR in previous work. The calculated free energy differences reveal that the methyl-substituted compounds are thermodynamically more stable than the primary compounds (8-methylpterin and 8-methyl-N5-deazapterin) when bound to the enzyme, due largely to hydrophobic hydration phenomena. Methyl substitution at the 5 and/or 7 positions in the 6-methyl-substituted compounds has only a small effect on the stability of ligand binding. Furthermore, repulsive interactions between the 6-methyl substituent and DHFR are minimal, suggesting that the 6-methyl position is optimal for binding. The results also show that similarly substituted 8-methylpterins and 8-methyl-N5-deazapterins have very similar affinities for binding to DHFR. The computer simulation predictions are in broad agreement with experimental data obtained from kinetic studies, i.e. 6,8-dimethylpterin is a more efficient substrate than 8-methylpterin and 6,8-dimethyl-N5-deazapterin is a better inhibitor than 8-methyl-N5-deazapterin.

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References

  1. Blakley, R.L., In Blakley, R.L. and Benkovic, S.J. (Eds.) Folates and Pterins-Chemistry and Biochemistry of Folates, Vol. 1, Wiley, New York, 1984, pp. 191–253.

    Google Scholar 

  2. Kraut, J. and Matthews, D.A., In Jurnak, F.A. and McPherson, A. (Eds.) Biological Macromolecules and Assemblies, Vol. 3, Wiley, New York, 1987, pp. 1–72.

    Google Scholar 

  3. Thibault, V., Koen, M.J. and Gready, J.E., Biochemistry 28 (1989) 6042.

    Google Scholar 

  4. Gready, J.E., In Curtius, H.-Ch., Ghisla, S. and Blau, N. (Eds.) Chemistry and Biology of Pteridines 1989, de Gruyter, Berlin, 1990, pp. 23–30.

    Google Scholar 

  5. Koen, M.J., Haynes, R.K., Gready, J.E. and Pilling, P.A., In Curtius, H.-Ch., Ghisla, S. and Blau, N. (Eds.) Chemistry and Biology of Pteridines 1989, de Gruyter, Berlin, 1990, pp. 94–97.

    Google Scholar 

  6. Cummins, P.L. and Gready, J.E., Proteins: Struct. Funct. Genet., in press.

  7. Jeong, S.S., Wormell, P. and Gready, J.E., In Blau, N., Curtius, H.-Ch., Levine, R. and Yim, J. (Eds.) Pteridines and Related Biogenic Amines and Folates, Hanrim, Seoul, 1992, pp. 277–292.

    Google Scholar 

  8. Gready, J.E., Ivery, M.T.G., Koen, M.J. and Yang, H.J., In Blau, N., Curtius, H.-Ch., Levine, R. and Yim, J. (Eds.) Pteridines and Related Biogenic Amines and Folates, Hanrim, Seoul, 1992, pp. 265–276.

    Google Scholar 

  9. Koen, M.J. and Gready, J.E., J. Org. Chem., 58 (1993) 1104.

    Google Scholar 

  10. Gready, J.E., J. Comput. Chem., 6 (1985) 377.

    Google Scholar 

  11. Gready, J.E., Biochemistry 24 (1985) 4761.

    Google Scholar 

  12. Williams, M.L. and Gready, J.E., J. Comput. Chem., 10 (1989) 35.

    Google Scholar 

  13. Jordan, M.J. and Gready, J.E., J. Comput. Chem. 10 (1989) 186.

    Google Scholar 

  14. Brown, D.J. and Jacobsen, N.W., J. Chem. Soc., (1961) 4413.

  15. Pfleiderer, W., In Blakley, R.L. and Benkovic, S.J. (Eds.) Folates and Pterins-Chemistry and Biochemistry of Pterins, Vol. 2, Wiley, New York, 1985, pp. 43–114.

    Google Scholar 

  16. Gready, J.E., to be published.

  17. Stone, S.R., Montgomery, J.A. and Morrison, J.F., Biochem. Pharmacol., 33 (1984) 175.

    Google Scholar 

  18. Davies, J.F., Delcamp, T.J., Prendergast, N.J., Ashford, V.A., Freisheim, J.H. and Kraut, J., Biochemistry, 29 (1990) 9467.

    Google Scholar 

  19. Ivery, M.T.G. and Gready, J.E., In Ayling, J.E., Nair, M.G. and Baugh, C.M. (Eds.) Chemistry and Biology of Pteridines and Folates, Plenum Press, New York, 1993, in press.

    Google Scholar 

  20. Tembe, B.L. and McCammon, J.A., Comput. Chem., 8, (1984) 281.

    Google Scholar 

  21. Singh, U.C., Brown, F.K., Bash, P.A. and Kollman, P.A., J. Am. Chem. Soc., 109 (1987) 1607.

    Google Scholar 

  22. Singh, U.C., Proc. Natl. Acad. Sci. USA, 85, (1988) 4280.

    Google Scholar 

  23. Singh, U.C. and Benkovic, S.J., Proc. Natl. Acad. Sci. USA, 85 (1988) 9519.

    Google Scholar 

  24. Brooks, C.L., Int. J. Quantum Chem. Quantum Biol. Symp., 15 (1988) 221.

    Google Scholar 

  25. Brooks, C.L., and Fleischman, S.H., J. Am. Chem. Soc., 112, (1990) 3307.

    Google Scholar 

  26. Fleischman, S.H. and Brooks, C.L., Proteins: Struct. Funct. Genet., 7 (1990) 52.

    Google Scholar 

  27. McDonald, J.J. and Brooks, C.L., J. Am. Chem. Soc., 113 (1991) 2295.

    Google Scholar 

  28. Volz, K.W., Matthews, D.A., Alden, R.A., Freer, S.T., Hansch, C., Kaufman, B.T. and Kraut, J., J. Biol. Chem., 257 (1982) 2528.

    Google Scholar 

  29. Matthews, D.A., Bolin, T.J., Burridge, J.M., Filman, D.J., Volz, K.N., Kaufman, B.T., Beddell, C.R., Champness, J.N., Stammers, D.K. and Kraut, J., J. Biol. Chem., 260 (1985) 381.

    Google Scholar 

  30. Matthews, D.A., Oatley, S.J. and Kraut, J., unpublished results for clDHFR·NADP+·biopterin complex.

  31. McTigue, M.A., DaviesII, J.F., Kaufman, B.T. and Kraut, J., Biochemistry, 31 (1992) 7264.

    Google Scholar 

  32. VanGunsteren, W.F., Prot. Eng., 2 (1988) 5.

    Google Scholar 

  33. VanGunsteren, W.F., In vanGunsteren, W.F. and Weiner, P.K. (Eds.) Computer Simulation of Biomolecular Systems, ESCOM, Leiden, 1989, pp. 27–59.

    Google Scholar 

  34. Pettitt, B.M., In vanGunsteren, W.F. and Weiner, P.K. (Eds.) Computer Simulation of Biomolecular Systems, ESCOM, Leiden, 1989, pp. 94–100.

    Google Scholar 

  35. Pearlman, D.A. and Kollman, P.A., In vanGunsteren, W.F. and Weiner, P.K. (Eds.) Computer Simulation of Biomolecular Systems, ESCOM, Leiden, 1989, pp. 101–119.

    Google Scholar 

  36. Pearlman, D.A. and Kollman, P.A., J. Am. Chem. Soc., 113 (1991) 7167.

    Google Scholar 

  37. Weiner, S.J., Kollman, P.A., Nguyen, D.T. and Case, D.A., J. Comput. Chem., 7 (1986) 230.

    Google Scholar 

  38. Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Ghio, C., Alagona, G., Profeta, S. and Weiner, P.K., J. Am. Chem. Soc., 106 (1984) 765.

    Google Scholar 

  39. Cummins, P.L., Ramnarayan, K., Singh, U.C. and Gready, J.E., J. Am. Chem. Soc., 113 (1991) 8247.

    Google Scholar 

  40. Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W. and Klein, M.L., J. Chem. Phys., 79 (1983) 926.

    Google Scholar 

  41. Dewar, M.J.S., Zoebisch, E.G., Healy, E.F. and Stewart, J.J.P., J. Am. Chem. Soc., 107 (1985) 3902.

    Google Scholar 

  42. Cummins, P.L. and Gready, J.E., Chem. Phys. Lett., 174 (1990) 355.

    Google Scholar 

  43. Hagler, A.T., Maple, J.R., Thacher, T.S., Fitzgerald, G.B. and Dinur, U., In vanGunsteren, W.F. and Weiner, P.K. (Eds.) Computer Simulation of Biomolecular Systems, ESCOM, Leiden, 1989, pp. 149–167.

    Google Scholar 

  44. Mezei, M. and Beveridge, D.L., Ann. N.Y. Acad. Sci., 482 (1986) 1.

    Google Scholar 

  45. Singh, U.C., Weiner, P.K., Caldwell, J.W. and Kollman, P.A., AMBER (Version 3.2), Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 1988.

    Google Scholar 

  46. Rao, B.G. and Singh, U.C., J. Am. Chem. Soc., 111 (1989) 3125.

    Google Scholar 

  47. VanGunsteren, W.F. and Berendsen, H.J.C., Mol. Phys., 34 (1977) 1311.

    Google Scholar 

  48. Brooks, C.L., Brunger, A. and Karplus, M., Biopolymers, 24 (1985) 843.

    Google Scholar 

  49. This version of NEWTON has been locally modified to perform direct averaging of coordinates.

  50. Ferrin, T., Huang, C., Pettersen, E.F., Couch, G.S. and Jarvis, L., MidasPlus program, Computer Graphics Laboratory, University of California, San Francisco, CA, 1989.

    Google Scholar 

  51. Bystroff, C., Oatley, S.J. and Kraut, J., Biochemistry, 29, (1990) 3263.

    Google Scholar 

  52. Mezei, M., J. Comput. Phys., 68 (1987) 237.

    Google Scholar 

  53. Solmajer, T. and Mehler, E.L., Prot. Eng. 4 (1991) 911.

    Google Scholar 

  54. Solmajer, T. and Mehler, E.L., Int. J. Quantum Chem., 44 (1992) 291.

    Google Scholar 

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  1. Department of Biochemistry, University of Sydney, 2006, Sydney, N.S.W., Australia

    Peter L. Cummins & Jill E. Gready

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  1. Peter L. Cummins
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Cummins, P.L., Gready, J.E. Computer-aided drug design: A free energy perturbation study on the binding of methyl-substituted pterins and N5-deazapterins to dihydrofolate reductase. J Computer-Aided Mol Des 7, 535–555 (1993). https://doi.org/10.1007/BF00124361

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  • DOI: https://doi.org/10.1007/BF00124361

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