QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3K\u03b3) inhibitors using MLR and ANN methods

Abstract

Phosphorylation of PI3Kγ as a member of lipid kinases-enzymes, plays a crucial role in regulating immune cells through the generation of intracellular signals. Deregulation of this pathway is involved in several tumors. In this research, diverse sets of potent and selective isoform-specific PI3Kγ inhibitors whose drug-likeness was confirmed based on Lipinski’s rule of five were used in the modeling process. Genetic algorithm (GA)-based multivariate analysis was employed on the half-maximal inhibitory concentration (IC50) of them. In this way, multiple linear regression (MLR) and artificial neural network (ANN) algorithm, were used to QSAR models construction on 245 compounds with a wide range of pIC50 (5.23–9.32). The stability and robustness of the models have been evaluated by external and internal validation methods (R2 0.623–0.642, RMSE 0.464–0.473, F 40.114, Q2LOO 0.600, and R2y-random 0.011). External verification using a wide variety of structures out of the training and test sets show that ANN is superior to MLR. The descriptors entered into the model are in good agreement with the X-ray structures of target-ligand complexes; so the model is interpretable. Finally, Williams plot-based analysis was applied to simultaneously compare the inhibitory activity and structural similarity of training, test and validation sets.