Discovery of New Phosphoinositide 3-kinase Delta (PI3Kδ) Inhibitors via Virtual Screening using Crystallography-derived Pharmacophore Modelling and QSAR Analysis

Background: PI3K delta is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3K delta inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3K delta binding. Methods: Seventeen PI3K delta crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors). Results: The best QSAR model (r(2) = 0.71, r(LOO)(2) = 0.70, r(press)(2) against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3K delta inhibitors. Two hits showed low micromolar IC50 values. Conclusion: Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3K delta inhibitors.