CoMFA and CoMSIA analysis of protein kinase B (PKBβ) inhibitors using various alignment methods

Abstract

Protein kinase B (PKB) is considered as a key mediator of proliferation and survival pathways, which involved in the development of several human cancers. PKB is a recognized target for the development of small-molecule inhibitors for the treatment of cancer. In this study a diverse set of 73 PKBβ inhibitors were aligned by three different methods (pharmacophore, docking-based, and rigid body alignment) for CoMFA and CoMSIA analysis. The best 3D QSAR models were obtained using pharmacophore-based alignment. CoMFA and CoMSIA models were found statistically significant with leave-one-out correlation coefficients (q2) of 0.613 and 0.562 respectively, cross-validated coefficients (r2cv) of 0.609 and 0.558, respectively and conventional coefficients (r2) of 0.914 and 0.989, respectively. 3D QSAR models were validated by a test set of 12 compounds giving satisfactory predicted correlation coefficients (r2pred) of 0.767 and 0.622 for CoMFA and CoMSIA models, respectively. This study provides valuable clues to design new compounds against PKBβ.