3D QSAR and HQSAR analysis of protein kinase B (PKB/Akt) inhibitors using various alignment methods

Abstract

Protein kinase B (PKB/Akt) regulates all aspects of cell growth, differentiation, and division. PKB/Akt has recently garnered a great deal of attention as a promising molecular target for cancer therapy due to its involvement in the development of several human cancers. In this study a diverse set of 56 Akt1 inhibitors were aligned by three different methods (pharmacophore-, docking- based and rigid body alignment) for CoMFA, CoMSIA and HQSAR analysis. The best QSAR models were obtained using rigid body alignment (Distill). CoMFA and CoMSIA models were found statistically significant with leave-one-out correlation coefficient (q2) of 0.627 and 0.598, respectively, cross validated coefficient (r2 cv) of 0.644 and 0.563, respectively, and conventional coefficient (r2) of 0.867 and 0.865, respectively. QSAR models were validated by a test set of 9 compounds giving satisfactory predicted correlation coefficient (r2 pred) of 0.603 and 0.613 for CoMFA and CoMSIA models, respectively. Leave-one-out correlation value (q2) of 0.687, r2 pred of 0.742 and r2 of 0.868 were obtained for HQSAR analysis and found satisfactory. This study provides valuable clues to design new compounds against PKB/Akt.