Modified CoMFA methods for the analysis of antineoplastic effects of lignan analogues

We have developed a modification of CoMFA that allows the method to deal with limited conformational mobility. We tried a number of weighting schemes, including simple average, Boltzman-weighted average and a variability-weighted average of conformer CoMFA fields to produce an overall field for each molecule, the most successful being the simple average field. We have applied the method to partially rigid, C-and D-ring modified lignan natural product derivatives related to podophyllotoxin, and the biological activities of these as measured against HT29, P388 and A549 cell lines. The modified CoMFA produces more robust regressions than "standard" CoMFA. The results of the modified CoMFA appear reliable enough to suggest that at least some of these compounds act through more than one mechanism, and that the importance of each mechanism appears to depend on the cell line used. (C) 2000 Elsevier Science B.V. All rights reserved.