4D-QSAR analysis of a set of ecdysteroids and a comparison to CoMFA modeling

The ecdysteroid-responsive Drosophila melanogaster BI, cell line is a prototypical homologous inducible gene expression system. A training set of 71 ecdysteroids, for which the -log(EC50) potencies in the ecdysteroid-responsive BI, 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 sidechain 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[EC50] 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).