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

• DOI: 10.1021/acsinfecdis.0c00566
• Publication Date: 2020-09-23T17:19:05Z
• Authors: Stephen Fienberg; Charles J. Eyermann; Lauren B. Arendse; Gregory S. Basarab; Jacob A. McPhail; John E. Burke; Kelly Chibale
• Keywords: Docking (animal); Homology

Plasmodium falciparum phosphatidylinositol 4-kinase (PfPI4K) has emerged as a promising new drug target for novel antimalarial therapeutics. In the absence of reliable high-resolution three-dimensional structure, homology model PfPI4K was built tool structure-based design. This been validated against three distinct chemical series potent inhibitors using docking and energy minimizations to elucidate interactions crucial PI4K inhibition antiplasmodium activity. Despite its potential an target, similarity between structurally related human kinases poses risk off-target kinase activity associated toxicity. Comparative phosphoinositide (PIKs) presents compelling evidence origins selectivity. in-depth analysis model, binding modes inhibitors, responsible selectivity over provides powerful template future optimization inhibitors.