Summary
An example of a CoMFA study is described with the aim to discuss one of the major problems of this 3D QSAR method: lack of variable selection. It is shown that the use of nonrelevant energy parameters might produce CoMFA contour maps which poorly reflect the actual nature of the binding site and are in part statistical artefacts. The data set employed in our analysis comparises triazine inhibitors of dihydrofolate reductase (DHFR), isolated from chicken liver, which have already been the object of a QSAR study by other authors. Since three-dimensional structures of triazine-DHFR complexes are known, it was possible not only to reduce ambiguities in the superimposition of the ligands, but also to compare the resulting CoMFA contour maps with the enzyme active site.
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References
CramerIII R.D., Patterson D.E. and Bunce J.D., J. Am. Chem. Soc., 110 (1988) 5959.
Martin Y.C., In Grunewald G.L. (Ed.) Quantitative Drug Design: A Critical Introduction, Medicinal Research Series, Vol. 8, Marcel Dekker, New York, NY, 1978.
Hansch C., Hathaway B.A., Guo Z., Selassie C.D., Dietrich S.W., Blaney J.M., Langridge R., Volz K.W. and Kaufman B.T., J. Med. Chem., 27 (1984) 129.
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.
Dietrich S.W., Blaney J.M., Reynolds M.A., Jow P.Y.C. and Hansch C., J. Med. Chem., 23 (1980) 1205.
SYBYL Molecular Modeling System (version 5.41), TRIPOS Associates, St. Louis, MO.
Stewart J.J.P., J. Comput. Chem., 10 (1989) 209.
MOPAC (version 5.00), Quantum Chemistry Program Exchange, No. 455, 1989.
Vinter J.G., Davis A. and Saunders M.R., J. Comput.-Aided Mol. Design, 1 (1987) 31.
Stahle L. and Wold S., Prog. Med. Chem., 25 (1988) 292.
Clark M., CramerIII R.D., Jones D.M., Patterson D.E. and Simeroth P.E., Tetrahedron Comput. Methodol., 3 (1990) 47.
CramerIII R.D., Bunce J.D., Patterson D.E. and Frank I.E., Quant. Struct.-Act. Relatsh., 7 (1988) 18.
Hansch C. and Leo A., In Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley, New York, NY, 1979.
Charton M., In Roche E.B. (Ed.) Design of Biopharmaceutical Properties through Prodrugs and Analogues, American Pharmaceutical Association, Washington, DC, 1977, p. 228.
Kim K.H. and Martin Y.C., J. Org. Chem., 56 (1991) 2723.
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Supplementary material available: The Cartesian coordinates and the atomic charges of the PM3-optimized structures used in the CoMFA study are available as MOL2 files upon request.
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Greco, G., Novellino, E., Pellecchia, M. et al. Effects of variable selection on CoMFA coefficient contour maps in a set of triazines inhibiting DHFR. J Computer-Aided Mol Des 8, 97–112 (1994). https://doi.org/10.1007/BF00119861
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DOI: https://doi.org/10.1007/BF00119861