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Abstract

The ecdysteroid agonist activity of 71 HPLC-purified ecdysteroids was measured in the Drosophila melanogaster BII tumorous blood cell line assay. The resultant log(ED50) values, spanning almost 6 orders of magnitude, were used to construct a comparative molecular field analysis (CoMFA) model in which conformations were selected by homology to the crystal structure of ecdysone. Model A was constructed by utilization of the region-focused electrostatic indicator field (q2 = 0.631, r2 = 0.903, 5 components, 4 outliers). Model B made use of region-focused electrostatic and steric indicator fields along with MlogP (q2 = 0.694, r2 = 0.892, 5 components, 4 outliers). The model and its underlying bioassay data support a pharmacophore hypothesis in which ecdysteroid binding is understood to be due principally to the summation of localized interactions from approximately six specific loci. This is in contrast to previous structure-activity relationship hypotheses which are formulated in terms of the presence or absence of essential functional groups, without which ecdysteroid receptor affinity would be completely absent. The present CoMFA model is utilized to predict the activities of heretofore unknown ecdysteroids.

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

“…In fact, the calculated relative solvation free energies for 20E, E, 22deoxy20E, and ponA (Table 2) indicate that the desolvation costs of the 20-and 22-hydroxyl groups are much lower than that of the 25-OH group. Consistent with this are results of Comparative Molecular Field Analysis (CoMFA) data that suggest that the 20-and 22-OH groups have stabilizing effects on ligand-receptor complex formation, whereas the 25-OH group has a destabilizing contribution (37). As a consequence, even though E, 22deoxy20E, and ponA each have two hydroxyl groups in their aliphatic tail (Table 2), ponA is poised to have an increased affinity for the receptor with respect to ligands such as E or 22deoxy20E, because the adjacent hydroxyl in ponA has a lower desolvation cost than the separate hydroxyls of E or 22deoxy20E.…”

“…2). In contrast to the 25-OH, the 20-and 22-hydroxyl groups contribute favorably to the affinity of 20E for the receptor as judged from the lower experimental activities of E (100-fold lower) and 22deoxy20E (3-fold lower) compared with that of 20E (37). Because no x-ray crystal structure of EcR in complex with E and 22deoxy20E is available, we made the assumption that these two ligands have similar conformations and similar binding modes to the receptor, except, of course, for the specific H-bonds made between the hormone and the receptor, for example, the H-bond observed in the complex between the 20-OH of 20E and Tyr 408 , which could not be formed with E that lack the 20-OH group.…”

“…The 20-and 22-OH groups are known to be essential for EcR binding of ecdysteroid ligands, and the removal of either the 20-or 22-OH group leads to a significant decrease in the ligand activity; this is in contrast to what is observed for the removal of the 25-OH group (37). The solvation free energies were determined using continuum electrostatics, as described above for 20E and ponA.…”

Structure-activity relationship studies of insect and plant steroid hormones

“…brassinolide BL 7) 1982 Castanea crenata castasterone CS 8) BL CS 70 9) brassinosteroid; BR 10,11) ES 12) BR 13 15) ES BR ES BR …”

Structure-activity relationship studies of insect and plant steroid hormones

“…hydroxy groups at position C-2, C-3, and C-22, as well as a carbonyl group at C-6. Although the structureactivity relationship between ESs and the molting hormone receptor binding activity, 12) as well as between BRs and the plant hormonal activity, [13][14][15] have been extensively investigated, it still remains unclear how insects and plants are able to distinguish those structurally closely related steroidal compounds and use them as hormones. In order to address this issue, we designed and synthesized a series of novel ESs and BRs derivatives, and evaluated their insect molting and plant hormonal activity.…”