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.
Every year, malaria caused by Plasmodium falciparum leads to 1 million deaths. Disease condition is alarming due to acquired resistance in parasite against antimalarial drugs in circulation. It brings the necessity to design novel inhibitors against newly identified drug targets. RIO-2 kinase regulates ribosome biogenesis and represents a promising drug target. Northeastern region of India is a biodiversity hub with a rich source of medicinal plants. Medicinal plants represent a source of phytochemical library to be screened to develop an inhibitor against the PfRIO-2 kinase. In current report, we selected plants with known antimalarial activity and performed in silico screening with phytochemicals against PfRIO-2 as a target. The majority of antimalarial phytochemicals docked very well into the ATP binding pocket of the PfRIO-2 kinase. A competition assay with substrate ATP indicates that a total of 5 phytochemicals, rutin, bebeerines, isochondrodendrine, nimbin and punicalagin, share similar interactions with protein residues within the ATP binding pocket and have potential to inhibit ATP binding. A significant relationship was found between docking energy and experimentally determined antimalarial values of rutin, bebeerines, isochondrodendrine, nimbin and punicalagin (R 2 = 0.91, p \ 0.001). Docking and virtual screening has identified lead phytochemicals, namely rutin, bebeerines, isochondrodendrine, nimbin and punicalagin, as a potent PfRIO-2 inhibitor, but cannot replace experimental verification. We are hopeful that the current study will help to understand the antimalarial action of the phytochemicals and design effective chemotherapy against malaria.
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