Structural Basis for Inhibitor Potency and Selectivity of Phosphatidylinositol 4-Kinase Inhibitors.

phosphatidylinositol 4-kinase (PI4K) has emerged as a promising new drug target for novel antimalarial therapeutics. In the absence of a reliable high-resolution three-dimensional structure, a homology model of PI4K was built as a tool for structure-based drug design. This homology model has been validated against three distinct chemical series of potent inhibitors using docking and energy minimizations to elucidate the interactions crucial for PI4K inhibition and potent antiplasmodium activity. Despite its potential as an antimalarial target, the similarity between PI4K and structurally related human kinases poses a risk for human off-target kinase activity and associated toxicity. Comparative docking between PI4K and human phosphoinositide kinases (PIKs) presents compelling evidence for the origins of selectivity. This in-depth analysis of the PI4K homology model, the binding modes of the inhibitors, and the interactions responsible for selectivity over human kinases provides a powerful template for future optimization of PI4K inhibitors.