Summary
Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/Ki), with an explained variance r2 of 0.885, and a cross-validated q2 of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q2 for one component was 0.62 and 0.61, respectively, while r2 was 0.674. We demonstrate that the predictive r2 based on the mean activity (Ym) of the training set is misleading, while the test set Ym-based predictive r2 index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.
Similar content being viewed by others
References
Ganong, W.F., Review of Medical Physiology, 16th ed., Appleton and Lange, Norwalk, CT, 1993, p. 780.
Chen, S., Besman, M.J., Shively, J.E., Yanagibashi, K. and Hall, P.F., Drug Metab. Rev., 20 (1989) 511.
Kellis, J.J. and Vickery, L.E., J. Biol. Chem., 262 (1987) 4413.
Thompson, E.A.J. and Siiteri, P.K., J. Biol. Chem., 249 (1974) 5373.
Brodie, A.M.H., Brodie, H.B., Callard, G., Robinson, C., Roselli, C. and Santen, R., J. Steroid Biochem. Mol. Biol., 44 (1993) 321.
Brodie, A.M.H. and Santen, R.J., Breast Cancer Res. Treat., 30 (1994) 1.
Brodie, A.M.H., J. Steroid Biochem. Mol. Biol., 49 (1994) 281.
Hervey, H.A., Lipton, A. and Santen, R.J., Cancer Res. (Suppl.), 42 (1982) 3261s.
Reed, M.J., Breast Cancer Res. Treat., 30 (1994) 7.
Strobl, J.S., In Craig, C.R. and Stitzel, R.E. (Eds.) Modern Pharmacology, 4th ed., Little, Brown and Co., Boston, MA, 1994 pp. 747–759.
Hartmann, R.W., Bayer, H. and Grun, G., J. Med. Chem., 37 (1994) 1275.
Chen, S. and Zhou, D., J. Biol. Chem., 267 (1992) 22587.
Chen, S., Zhou, D., Swiderek, K., Kadohama, N., Osawa, Y. and Hall, P.F., J. Steroid Biochem. Mol. Biol., 44 (1993) 347.
Amarnch, B., Corbin, C.J., Peterson, J.A., Simpson, E.R. and Graham-Lorence, S., Mol. Endocrinol., 7 (1993) 1617.
Kadohama, N., Yarborough, C., Zhou, D., Chen, S. and Osawa, Y., J. Steroid Biochem. Mol. Biol., 43 (1992) 693.
Zhou, D., Pompon, D. and Chen, S., Proc. Natl. Acad. Sci. USA, 88 (1991) 410.
Zhou, D., Korzekwa, K.R., Poulos, T. and Chen, S., J. Biol. Chem., 267 (1992) 762.
Zhou, D., Cam, L.L., Laughton, C.A., Korzekwa, K.R. and Chen, S.U., J. Biol. Chem., 269 (1994) 19501.
Laughton, C.A., Zvelebil, M.J.J.M. and Neidle, S., J. Steroid Biochem. Mol. Biol., 44 (1993) 399.
Poulos, T.L., Finzel, B.C. and Howard, A.J., J. Mol. Biol., 195 (1987) 687.
Oprea, T.I., Ho, C.M.W. and Marshall, G.R., In Reynolds, C.H., Holloway, M.K. and Cox, H.K. (Eds.) Computer-Aided Molecular Design, ACS Symposium Series Vol. 589, Washington, DC, 1995, pp. 64–81.
Green, S.M. and Marshall, G.R., Trends Pharmacol. Sci., 16 (1995) 285.
Cramer III, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.
Numazawa, M., Mutsumi, A., Hoshi, K. and Koike, R., Biochem. Biophys. Res. Commun., 160 (1989) 1009.
Numazawa, M., Mutsumi, A., Hoshi, K., Oshibe, M., Ishikawa, E. and Kigawa, H., J. Med. Chem., 34 (1991) 2496.
Numazawa, M. and Mutsumi, A., Biochem. Biophys. Res., Commun., 177 (1991) 401.
Numazawa, M. and Oshibe, M., J. Med. Chem., 37 (1994) 1312.
Numazawa, M., Mutsumi, A., Tachibana, M. and Hoshi, K., J. Med. Chem., 37 (1994) 2198.
Baroni, M., Costantino, G., Cruciani, G., Riganelli, D., Valigi, R. and Clementi, S., Quant. Struct.-Act. Relatsh., 12 (1993) 9.
Topliss, J.G. and Costello, R.J., J. Med. Chem., 15 (1972) 1066.
Cramer III, R.D. and Bunce, J.D., In Hadzi, D. and Jerman-Blazic, B. (Eds.) QSAR in Drug Design and Toxicology, Elsevier, Amstdrdam, The Netherlands, 1987, pp. 3–12.
Wold, S., Johansson, E. and Cocchi, M., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, The Netherlands, 1993, pp. 523–550.
Wold, S., Esbensen, K. and Geladi, P., Chemometrics Intelligent Lab. Syst., 2 (1987) 37.
Cramer III, R.D., Bunce, J.D., Patterson, D.E. and Frank, I.E., Quant. Struct.-Act. Relatsh., 7 (1988) 18.
Cruciani, G., Baroni, M., Clementi, S., Costantino, G., Riganelli, D. and Skagerberg, B., J. Chemometrics, 6 (1992) 335.
Cramer III, R.D., DePriest, S.A., Patterson, D.E. and Hecht, P., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Application, ESCOM, Leiden, The Netherlands, 1993, pp. 443–485.
Waller, C.L., Oprea, T.I., Giolitti, A. and Marshall, G.R., J. Med. Chem., 36 (1993) 4152.
Oprea, T.I., Waller, C.L. and Marshall, G.R., J. Med. Chem., 37 (1994) 2206.
Goodford, P.J., J. Am. Chem. Soc., 28 (1985) 849.
Cruciani, G., Clementi, S. and Baroni, M., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, The Netherlands, 1993, pp. 551–564.
Cruciani, G. and Watson, K.A., J. Med. Chem., 37 (1994) 2589.
Martin, Y., Bures, M., Danaher, E. and DeLazzer, J., In Wermuth, C.G. (Ed.). Trends in QSAR and Molecular Modelling 92 (Proceedings of the 9th European Symposium on Structure-Activity Relationships: QSAR and Molecular Modelling), ESCOM, Leiden, The Netherlands, 1993, pp. 20/2-27.
Jain, A.N., Koile, K. and Chapman, D., J. Med. Chem., 37, (1994) 2315.
Vinter, J., J. Comput.-Aided Mol. Design, 8 (1994) 653.
Oprea, T.I. and Vinter, J.G., In Sanz, F. (Ed.) Proceedings of the 10th European QSAR Symposium, J.R. Prous, Barcelona, Spain, 1995, in press.
Appelt, K., Perspect. Drug Discov. Design, 1 (1993) 23.
Arevalo, J.H., Taussig, M.J. and Wilson, I.A., Nature, 365 (1993) 859.
Stewart, J.J.P., J. Comput.-Aided Mol. Design, 4 (1990) 1.
Weisberg, S., Applied Linear Regression, 2nd ed., Wiley, New York, NY, 1985, pp. 196–239.
Oprea, T.I., Waller, C.L. and Marshall, G.R., Drug Des. Discov., 12 (1994) 29.
Brueggemeier, R.W., Li, P.-K., Moh, P.P. and Katlic, N.E., J. Steroid Biochem. Mol. Biol., 37 (1990) 379.
Li, P.-K. and Brueggemeier, R.W., J. Med. Chem., 33 (1990) 101.
Li, P.-K. and Brueggemeier, R.W., J. Steroid Biochem. Mol. Biol., 36 (1990) 533.
Brueggemeier, R.W., Moh, P.P., Ebrahimian, S. and Darby, M.V., J. Steroid Biochem. Mol. Biol., 44 (1993) 357.
Burkhart, J.P., Peet, N.P., Wright, C.L. and Johnston, J.O., J. Med. Chem., 34 (1991) 1748.
Peet, N.P., Johnston, J.O., Burkhart, J.P. and Wright, C.L., J. Steroid Biochem. Mol. Biol., 44 (1993) 409.
Johnston, J.O., Wright, C.L., Burkhart, J.P. and Peet, N.P., J. Steroid Biochem. Mol. Biol., 44 (1993) 623.
DiSalle, E., Briatico, G., Giudici, D., Ornati, G., Zaccheo, T., Buzzetti, F., Nesi, M. and Panzeri, A., J. Steroid Biochem. Mol. Biol., 49 (1994) 289.
DiSalle, E., Giudici, D., Ornati, G., Briatico, G., D'Alessio, R., Villa, V. and Lombardi, P., J. Steroid Biochem. Mol. Biol., 37 (1990) 369.
Abul-Hajj, Y.J., J. Steroid Biochem., 35 (1990) 139.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Oprea, T.I., García, A.E. Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors. Journal of Computer-Aided Molecular Design 10, 186–200 (1996). https://doi.org/10.1007/BF00355042
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00355042