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

Abstract

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 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 of 0.954. A test set of 18 compounds was used to validate the predictive ability of the two models. The predicted correlation coefficients 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.

Keywords:

• progesterone receptor
• comparative molecular field analysis (CoMFA)
• comparative molecular similarity indices analysis (CoMSIA)
• inhibitor
• QSAR

Acknowledgements

This work was supported by Independent Innovation Foundation of Shandong University (2009JC018), Graduate Independent Innovation Foundation of Shandong University (yzc11035) and Virtual Laboratory of School of Pharmaceutical Sciences, Shandong University.