Receptor-based QSAR study for a series of 3,3-disubstituted-5-aryl oxindoles and 6-aryl benzimidazol-2-ones derivatives as progesterone receptor inhibitors
Receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 54 progesterone receptor (PR) inhibitors. The established CoMFA model from the training set gives statistically significant results with the cross-validated q(2) of 0.534 and non-cross-validated r(ncv)(2) of 0.947. The best CoMSIA model was derived by the combination of steric field and hydrophobic field with a q(2) of 0.615 and r(ncv)(2) of 0.954. A test set of 18 compounds was used to validate the predictive ability of the two models. The predicted correlation coefficients r(pred)(2) are 0.681 and 0.677 for CoMFA and CoMSIA models, respectively. Based on the CoMFA maps, the key structural characters of progesterone receptor inhibitors are identified. Moreover, the binding modes of oxindoles and benzimidazol-2-ones are also given by the quantum mechanical/molecular mechanical (QM/MM) calculations. This may provide useful information for drug design.
qsar progesterone receptor inhibitor comparative molecular field analysis (comfa) comparative molecular similarity indices analysis (comsia)