Computational Docking Studies of Novel Heterocyclic Carboxamides as Potential PI3Kα Inhibitors

Drugs comprising a heterocyclic system show widespread therapeutic impact such as antimicrobial, antidepressant, antihypertensive, and anticancer activity. We describe herein computational studies that support the promising biological activity of four new compounds (5, 6, 10 and 13). The wild-type and mutant phosphatidylinositol-4,5-bisphosphate 3-kinasea (PI3K alpha) proteins were used as models to explore the potential interaction of the designed molecules with this important kinase involved in the growth regulation of cancer cells. The results of our studies showed that the verified compounds ought to fit into the kinase domain of wild-type and mutant PI3K alpha s. It is predicted that they interact with S774, K802, Y836, V851, S854, T856, Q859, and D933 that are known to be key binding residues for active inhibitors both in wild-type and mutant PI3Kas. Docking scores infer the selectivity of compounds 5, 6 and 10 toward the mutant PI3K alpha (H1047R), whereas compound 13 displayed a slightly higher affinity to the wild-type protein. The pharmacophore modeling of PI3K alpha inhibitors showed that the explored compounds shared four out of five pharmacophoric points with such inhibitors. Thus, the recently developed four compounds might be recruited as lead structures for the design of new antitumor drugs targeting PI3K alpha.