Summary
An empirical hydrophobic field-like 3D function has been calculated with the program HINT (hydrophobic interactions) and imported into the SYBYL implementation of CoMFA (Comparative Molecular Field Analysis). The addition of hydrophobicity appears to offer increased chemical interpretability of CoMFA models. An example is given using the steroid model reported by Cramer et al. (J. Am. Chem. Soc., 110 (1988) 5959). While addition of the HINT field did not improve statistical parameters in this model, the CoMFA coefficient contours from the hydrophobic field unambiguously define the most active steroid molecules in the chemical terms of hydrophobic and polar substituents.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Cramer, R.D.III, Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.
Thomas, B.F., Compton, D.R., Martin, B.R. and Semus, S.F., Mol. Pharmacol., in press.
Marshall, G.R., Mayer, D., Naylor, C.B., Hodgkin, E.E., Cramer, R.D.III, In Fauchere, J.-L. (Ed.) QSAR: Quantitative Structure-Activity Relationships in Drug Design, Alan R. Liss, New York, 1989, p. 287.
Allen, M.S., Tan, Y.-C., Trudell, M.L., Narayan, K., Schindler, L.R., Martin, M.J., Schultz, C., Hagen, T.J., Koehler, K.F., Codding, P.W., Skolnick, P. and Cook, J.M., J. Med. Chem., 33 (1990) 2343.
Norinder, U., J. Comput.-Aided Mol. Design, 4 (1990) 381.
Meyer, H., Arch. Exp. Pathol. Pharmakol., 42 (1899) 109.
Overton, E., Vierteljahrsschr. Naturforsch. Ges. Zürich, 44 (1899) 88.
hansch, C. and Fujita, T., J. Am. Chem. Soc., 88 (1964) 1616.
Rekker, R.F., The Hydrophobic Fragmental Constant: Its Derivation and Application. A Means of Characterizing Membrane Systems, Elsevier Science Publ., Amsterdam, 1977.
Hansch, C. and Leo, A.J., Substituent Constants for Correlation Analysis in Chemistry and Biology, J. Wiley and Sons, New York, 1979.
Abraham, D.J. and Leo, A.J., Proteins: Struct. Funct. Genetics, 2 (1987) 130.
Kellogg, G.E. and Abraham, D.J., Med. Chem. Res., submitted.
Wireko, F.C., Kellogg, G.E. and Abraham, D.J., J. Med. Chem., 34 (1991) 758.
Fauchere, J.-L., Quarendon, P. and Kaetterer, L., J. Mol. Graphics, 6 (1988) 203.
Wold, S., Ruhe, A., Wold, H. and Dunn, W. J.III, SIAM J. Sci. Stat. Comput., 5 (1984) 735.
Wold, S., Technometrics, 20 (1978) 397.
Kollman, P.A., In Wolff, M.E. (Ed.) Burger's Medicinal Chemistry, Part 1 (The Basis of Medicinal Chemistry), 4th edn., J. Wiley and Sons, New York, 1980, p. 313.
Franke, R., Theoretical Drug Design Methods, Elsevier, Amsterdam, 1984.
Available from Tripos Associates, 1699 South Hanley Road, St. Louis, MO 63144.
Cross-validated r2 (press, components) for 2 Å studies otherwise identical to those in Table 1: steric, 0.711 (0.747, 4); electrostatic, 0.694 (0.768, 2); hydrophobic, 0.643 (0.829, 1); steric/electrostatic, 0.744 (0.703, 5); steric/hydrophobic, 0.685 (0.779, 4); electrostatic/hydrophobic, 0.800 (0.621, 3); steric/electro./hydro., 0.794 (0.630, 5).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kellogg, G.E., Semus, S.F. & Abraham, D.J. HINT: A new method of empirical hydrophobic field calculation for CoMFA. J Computer-Aided Mol Des 5, 545–552 (1991). https://doi.org/10.1007/BF00135313
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00135313