Title:PfRIO-2 Kinase is a Potential Therapeutic Target of Antimalarial Protein Kinase Inhibitors
VOLUME: 10 ISSUE: 1
Author(s):Swagata Nag, KMN Prasad, Ananya Bhowmick, Rohitas Deshmukh and Vishal Trivedi
Affiliation:Malaria Research Group, Department of Biotechnology, Indian Institute of Technology-Guwahati Guwahati-781039, Assam, India.
Keywords:ATP, antimalarials, drug, inhibitors, kinase, RIO-2 kinase, Malaria
Abstract:Protein kinases (PKs) present in Plasmodium falciparum catalyze phosphorylation reaction to control growth
and differentiation of the parasite throughout the life cycle. Protein kinase inhibitors are found to kill the parasite but their
cellular target enzymes are not known. Protein kinase inhibitors are evaluated in an in sillico docking studies using plasmodium
falciparum RIO-2 kinase (right open reading frame-2 protein kinase) as target enzyme. Most of the protein kinase
inhibitors showed appropriate docking within the ATP binding domain of the PfRIO-2 kinase. The initial docking experiments
were further validated by a substrate competition experiment to validate the preliminary screening results and test
the potentials of these inhibitors under in vivo conditions. Docking and substrate competition study identifies wortmannin,
enzastaurin, indirubin-3'-monoxime, apigenin, kaempferol and 8-hydroxy-4-methyl-9-nitro-2H-benzo[g]chromen-2-one as
lead inhibitors against native/active form of the PfRIO-2 kinase. The top protein kinase inhibitors bind into the ATP binding
site with a similar conformation as ATP. The docking result is in good agreement with the antimalarial schizonticidal
IC50 (μg/ml) of an inhibitor and gives a correlation factor (R2) of 0.82 whereas top hit antimalarial inhibitors gives a correlation
factor (R2) of 0.99. In summary, our work highlights the importance of PfRIO-2 kinase as a target behind the antimalarial
action of protein kinase inhibitors and might help to design a new set of antimalarial remedies.
