Summary
Orientation of ten water molecules bound strongly at the contact surface of the dihydrofolate reductase-methotrexate enzyme-inhibitor complex was determined theoretically. To optimize the orientation of the water molecules, a recent method based on a simple electrostatic model was applied. The electrostatic complementarity in the binary complex was investigated using the lock-and-key model, considering the effect of the water molecules as well. The strongly bound water molecules improve the electrostatic fit in the pteridine region of methotrexate. Their role in the benzoic amide andγ-glutamate region is to decrease the internal energy by creating water bridges among remote polar sites making it possible to form H-bonds. Some modifications in the inhibitor structure were proposed for achieving greater inhibitor potency. The presumably enhanced effect is ascribed to the free energy gain in repelling the water molecules from the contact surface to the bulk of the solvent, and, in other cases, to internal energy decreases due to better electrostatic fit in the enzyme-inhibitor complex.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Blaney, J.M., Hansch, C., Silipo, C. and Vittoria, A., Chem. Rev., 84 (1984) 333–407.
Birdsall, B., Feeney, F., Pascual, C., Roberts, G.C.K., Kompis, I., Then, R.L., Mueller, K. and Kroehn, A., J. Med. Chem., 27 (1984) 1672–1676.
Kuyper, L.F., Roth, B., Baccanari, D.P., Ferone, R., Beddell, C.R., Champness, J.N., Stammers, D.K., Dann, J.G., Norrington, F.E., Baker, D.J. and Goodford, P.J., J. Med. Chem., 28 (1985) 303–311.
DesJarlais, R.L., Sheridan, R.P., Dixon, J.S., Kuntz, I.D. and Venkataraghavan, R., J. Med. Chem., 29 (1986) 2149–2153.
Mueller, K., Amman, H.J., Doran, D.M., Gerber, P. and Schrepfer, G., In Harms, A.F. (Ed.) Innovative Approaches in Drug Research, Elsevier Science Publishers, Amsterdam, 1986, pp. 125–134.
Hansch, C. and Klein, T.E., Acc. Chem. Res., 19 (1986) 392–400.
Komatsu, K., Nakamura, H., Nakagawa, S. and Umeyama, H., Chem. Pharm. Bull., 32 (1984) 3313–3316.
Sheridan, R.P. and Venkataraghavan, R., Acc. Chem. Res., 20 (1987) 322–329.
Gready, J.E., J. Mol. Struct. (THEOCHEM), 109 (1984) 231–244.
Richards, W.G. and Cuthbertson, A.F., J. Chem. Soc., Chem. Commun., (1984) 167–168.
Cuthbertson, A.F. and Richards, W.G., J. Chem. Res. (S), (1985) 354–355.
Cuthbertson, A.F. and Richards, W.G., J. Mol. Struct. (THEOCHEM), 134 (1986) 411–414.
Höltje, H.-D. and Zunker, P., J. Mol. Struct. (THEOCHEM), 134 (1986) 429–436.
Gready, J.E., Biochemistry, 24 (1985) 4761–4766.
Andrews, P.R., Sadek, M., Spark, M.J. and Winkler, D.A., J. Med. Chem., 29 (1986) 698–708.
Welsh, W.J. and Cody, V., In Cooper, B.A. and Whitehead, V.M. (Eds.) Chemistry and Biology of Pteridines 1986, Walter de Gruyter, Berlin, 1986, pp. 799–802.
Komatsu, K., Nakagawa, S., Umeyama, H. and Nakamura, H., Chem. Pharm. Bull., 35 (1987) 1880–1895.
Ghose, A.K. and Crippen, G.M., J. Med. Chem., 28 (1985) 333–346.
Mabilia, M., Pearlstein, R.A. and Hopfinger, A.J., Eur. J. Med. Chem. Chim. Ther., 20 (1982) 163–174.
Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650–13662.
Filman, D.J., Bolin, J.T., Matthews, D.A. and Kraut, J., J. Biol. Chem., 257 (1982) 13663–13672.
Finney, J.L., In Franks, F. (Ed.) Water, a Comprehensive Treatise, Vol. 6, Plenum Press, New York, 1979, pp. 47–138.
Warshel, A. and Russell, S.T., Q. Rev. Biophys., 17 (1984) 283–222.
Warshel, A., Russell, S. and Sussman, F., Isr. J. Chem., 27 (1986) 217–224.
Náray-Szabó, G. and Nagy, P., Enzyme, 36 (1986) 44–53.
Nagy, P., Angyán, J.G. and Náray-Szabó, G., J. Mol. Struct. (THEOCHEM), 149 (1987) 169–176.
Náray-Szabó, G. and Nagy, P., In Rein, R. (Ed.) Molecular Basis of Cancer, Part B, Alan R. Liss, New York, 1985, pp. 105–113.
Nagy, P. and Náray-Szabó, G., Can. J. Chem., 63 (1985) 1694–1698.
Bonaccorsi, R., Scrocco, E. and Tomasi, J., J. Chem. Phys., 52 (1970) 5270–5284.
Scrocco, E. and Tomasi, J., Top. Curr. Chem., 42 (1973) 95–170.
Srebrenik, S., Weinstein, H. and Pauncz, R., Chem. Phys. Lett., 20 (1973) 419–423.
Filman, D.J., Matthews, D.A., Bolin, J.T. and Kraut, J., Protein Data Bank File40SB13, 153 (1985).
Bernstein, F.C., Koetzle, T.F., Williams, G.T.B., Mayer, E.F., Brice, M.D., Rogers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535–542.
Angyán, J.G. and Náray-Szabó, G., Program PROTPOT, 1981, CHINOIN Pharmaceutical and Chemical Works, P.O. Box 110, H-1325 Budapest.
Angyán, J.G. and Náray-Szabó, G., J. Theor. Biol., 103 (1983) 349–356.
Náray-Szabó, G., Kramer, G., Nagy, P. and Kugler, S., J. Comput. Chem., 8 (1987) 555–561.
Nagy, P., J. Mol. Struct. (THEOCHEM), in press.
Náray-Szabó, G., Int. J. Quant. Chem., 16 (1979) 265–272.
Náray-Szabó, G., Grofcsik, K., Kósa, K., Kubinyi, M. and Martin, A., J. Comput. Chem., 2 (1981) 58–62.
Nagy, P., Angyán, J.G., Náray-Szabó, G. and Peinel, G., Int. J. Quant. Chem., 31 (1987) 927–939.
Kollman, P., McKelvey, J., Johansson, A. and Rothenberg, S., J. Am. Chem. Soc., 97 (1975) 955–965.
Kollman, P., J. Am. Chem. Soc., 99 (1977) 4875–4894.
Douglas, J.E. and Kollman, P.A., J. Am. Chem. Soc, 102 (1980) 4295–4302.
Jencks, W.P., Adv. Enzymol., 43 (1975) 219–410.
Andrews, P.R., Craik, D.J. and Martin, J.L., J. Med. Chem., 27 (1984) 1648–1657.
Bird, O.D., Vaitkus, J.W. and Clarke, J., Mol. Pharmacol., 6 (1970) 573–575.
Chaykowsky, M., Rosowsky, A., Papathanasopoulos, N., Chen, K.K.N., Modest, E.J., Kisliuk, R.L. and Gaumont, Y., J. Med. Chem., 17 (1974) 1212–1216.
Rosowsky, A. and Chen, K.K.N., J. Med. Chem., 17 (1974) 1308–1311.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nagy, P. Orientation and structure-building role of the water molecules bound at the contact surface of the dihydrofolate reductase-methotrexate complex. J Computer-Aided Mol Des 2, 65–76 (1988). https://doi.org/10.1007/BF01532054
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01532054