1. Structural Basis for Inhibitor Potency and Selectivity of Plasmodium falciparum Phosphatidylinositol 4-Kinase Inhibitors
- Author
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John E. Burke, Jacob A. McPhail, Charles J. Eyermann, Kelly Chibale, Stephen Fienberg, Gregory S. Basarab, and Lauren B. Arendse
- Subjects
0301 basic medicine ,Drug ,biology ,Chemistry ,Kinase ,media_common.quotation_subject ,030106 microbiology ,Plasmodium falciparum ,Computational biology ,biology.organism_classification ,3. Good health ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Infectious Diseases ,Docking (molecular) ,Potency ,Phosphatidylinositol ,Homology modeling ,Kinase activity ,media_common - Abstract
Plasmodium falciparum phosphatidylinositol 4-kinase (PfPI4K) 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 PfPI4K 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 PfPI4K and structurally related human kinases poses a risk for human off-target kinase activity and associated toxicity. Comparative docking between PfPI4K and human phosphoinositide kinases (PIKs) presents compelling evidence for the origins of selectivity. This in-depth analysis of the PfPI4K 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 Plasmodium PI4K inhibitors.
- Published
- 2020
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