4D-QSAR Analysis of a Set of Ecdysteroids and a Comparison to CoMFA Modeling

Abstract

The ecdysteroid-responsive Drosophila melanogaster B(II) cell line is a prototypical homologous inducible gene expression system. A training set of 71 ecdysteroids, for which the -log(EC(50)) potencies in the ecdysteroid-responsive B(II) cell line were measured, was used to construct 4D-QSAR models. Four nearly equivalent optimum 4D-QSAR models, for two modestly different alignments, were identified (Q(2) = 0.76-0.80). These four models, together with two CoMFA models, were used in consensus modeling to arrive at a three-dimensional pharmacophore. The C-2 and C-22 hydroxyls are identified as hydrogen-bond acceptor sites which enhance activity. A hydrophobic site near C-12 is consistent with increasing activity. The side-chain substituents at C-17 are predicted to adopt semiextended "active" conformations which could fit into a cylinder-shaped binding pocket lined largely with nonpolar residues for enhanced activity. A test set of 20 ecdysteroids was used to evaluate the QSAR models. Two 4D-QSAR models for one alignment were identified to be superior to the others based on having the smallest average residuals of prediction for the prediction set (0.69 and 1.13 -log[EC(50)] units). The correlation coefficients of the optimum 4D-QSAR models (R(2) = 0.87 and 0.88) are nearly the same as those of the best CoMFA model (R(2) = 0.92) determined for the same training set. However, the cross-validation correlation coefficient of the CoMFA model is less significant (Q(2) = 0.59) than those of the 4D-QSAR models (Q(2) = 0.80 and 0.80).

Semi‐Synthetic Ecdysteroids as Gene‐Switch Actuators: Synthesis, Structure–Activity Relationships, and Prospective ADME Properties

“…However, a 22-O-benzyl substituent (9) does not significantly decrease 20E potency, a result that recalls by analogy the moderately high responsiveness of the 20E 22-benzoyl derivative. [34] On the other hand, O-alkylation of PoA at any position decreases potency in this bioassay.…”

“…Estimation of ADME properties: The 1-octanol-water partition coefficients (Mlog P) [80] of ecdysteroid O-alkyl ether analogues were determined by scaling against previously calculated [34] Mlog P values of nonether ecdysteroids. Estimations of the Caco-2 cell permeation coefficients and the blood-brain barrier partition coefficients, were made using established membrane-interaction QSAR (MI-QSAR) models.…”

“…[28] Additionally, the specific H-bond acceptor/H-bond donor role of each of these hydroxy groups in EcR binding and geneswitch potency is not entirely transparent, in spite of the availability of crystal structures of several ligand-EcR complexes, [29][30][31][32] as well as multi-dimensional QSAR modelling. [33,34] Herein we report the first systematic synthetic exploration of ecdysteroids toward modulation of gene-switch potency. Hydroxy groups, individually and severally, were methylated or otherwise alkylated (Table 1).…”

The Ecdysteroidome of Drosophila: influence of diet and development

“…3D). Thus, dhMaA is a fully functional ecdysteroid in vivo, whereas 24-epi-MaA suffices for larval stages, but cannot support pupal development, consistent with its lower activity in tissue culture assays (Clément et al, 1993;Ravi et al, 2001). Thus, the ability of yeast-fed animals to selectively utilize 24 (28)-dehydroergosterol(s) for dhMaA synthesis is likely to be crucial for survival when feeding on yeast in the wild.…”

Investigation of plants containing unusual ecdysteroids with ring in their side-chain

“…15,16 The data obtained from such studies have led to a pharmacophore hypothesis for the interactions of ligands with the ecdysteroid receptor: it is postulated that the key molecular features responsible for the activity are not identical to the characteristic structural elements mentioned above. The structure-activity studies have revealed that a hydroxy group on C-2 acts as an H-bond acceptor, C-3 should be substituted, preferably with a polar negative atom, a hydroxy group on C-20 is an H-bond donor and a hydroxy group on C-22 is an H-bond acceptor.…”