An extensive ecdysteroid CoMFA

The ecdysteroid agonist activity of 71 HPLC-purified ecdysteroids was measu red in the Drosophila melanogaster B-II tumorous blood cell line assay. The resultant log(ED50) values, spanning almost 6 orders of magnitude, were us ed to construct a comparative molecular field analysis (CoMFA) model in whi ch conformations were selected by homology to the crystal structure of ecdy sone. Model A was constructed by utilization of the region-focused electros tatic indicator field (q(2) = 0.631, r(2) = 0.903, 5 components, 4 outliers ). Model B made use of region-focused electrostatic and steric indicator fi elds along with MlogP (q(2) = 0.694, r(2) = 0.892, 5 components, 4 outliers ). The model and its underlying bioassay data support a pharmacophore hypot hesis in which ecdysteroid binding is understood to be due principally to t he summation of localized interactions from approximately six specific loci . This is in contrast to previous structure-activity relationship hypothese s which are formulated in terms of the presence or absence of essential fun ctional groups, without which ecdysteroid receptor affinity would be comple tely absent. The present CoMFA model is utilized to predict the activities of heretofore unknown ecdysteroids.