Discovery of novel and highly selective PI3Kδ inhibitors based on the p110δ crystal structure.

Recently, more and more experts pay attention to the research and development of phosphoinositide 3-Kinase delta (PI3K?) inhibitions. PI3K? inhibition is one of the most attractive approaches for the treatment of autoimmune diseases and leukocyte malignancies. PI3K? selective inhibitors include propeller-shaped and flat inhibitors. Compared with flat inhibitors, propeller-shaped inhibitors have stronger PI3K? selectivity. With the aim of finding novel and highly selective PI3K? inhibitors, structural optimization of PI3K? propeller-shaped inhibitor (idelalisib) was executed based on the interaction mechanism between the PI3K? inhibitor and protein. Then, binding mode, pharmacokinetic properties and stabilities of ligand-protein complexes were predicted by computer technologies (molecular docking, ADMET prediction and molecular dynamics simulations). Finally, comp#1 with excellent properties was selected. After the SciFinder verification, comp#1 was a novel compound and had the value for further study. This work adds data to a well investigated area of discovering potential PI3K? inhibitors and promotes the research of mechanisms of PI3K? inhibitors.