Quasi 4D-QSAR and 3D-QSAR study of the pan class I phosphoinositide-3-kinase (PI3K) inhibitors

Abstract

The class I phosphoinositide-3-kinases (PI3Ks) is currently investigated and attracted as a promising target toward anticancer therapies. The quasi 4D-QSAR model is developed by a training set of 30 pan class I PI3K inhibitors. This methodology is based on the generation of a conformational ensemble profile for each compound instead of only one conformation, followed by the calculation of intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from molecular dynamic simulations. A comparison of the proposed methodology with comparative molecular field analysis (CoMFA) formalism has been performed. This paradigm explores jointly the main features of CoMFA and 4D-QSAR models. The best 4D-QSAR model is checked for free from chance correlation, reliability and robustness by leave-N-out cross-validation and Y-randomization in addition to analysis of the independent test set. Statistical parameters of the best 4D-QSAR model are R 2 = 0.871, q LOO 2 = 0.661, and R Pred 2 = 0.751. The results of the suggested model are in good agreement with docking study that was previously reported by Rewcastle et al. (J Med Chem 54:7105–7126, 2011).