Plasmodium falciparum FIKK 9.1 kinase modeling to screen and identify potent antimalarial agents from chemical...

The Plasmodium FIKK kinases are diverged from human kinases structurally. They harbour conserved ATP-binding domains that are non-homologous to other existing kinases. FIKK9.1 kinase is considered as an essential protein for parasite survival. It is localized in major organelles present in parasite and trafficked throughout the infected RBC. It is speculated that FIKK9.1 may phosphorylate several substrates in the parasite's proteome and contribute to parasite survival. Therefore, FIKK9.1 is an attractive target that may lead to a novel class of antimalarials. To identify specific FIKK9.1 kinase inhibitors, we virtually screened organic structural scaffolds from a library of 623 entries. The top hits were identified based on conformations and molecular interactions with the ATP biophore. The hits were also validated under in vitro conditions. In this study, we identified seven top hit organic compounds that may arrest the growth of parasites by inhibiting FIKK9.1 kinase. Evaluation of top hit compounds in antimalarial activity assay identifies that the highly substituted 1,3-selenazolidin-2-imine 1 and thiophene 2 are inhibiting parasite growth with an IC₅₀ of 3.2 ± 0.27 μg/ml and 3.13 ± 0.16 μg/ml, respectively. These functionalized heterocyclic compounds 1 and 2 kills the malaria parasite with an IC₅₀ of 2.68 ± 0.02 μg/ml and 3.08 ± 0.14 μg/ml, respectively. Isothermal titration calorimetry analysis indicate that ATP is binding to the FIKK9.1 kinase. The dissociation constant (K) is measured to be 27.8 ± 2.07 μM with a stoichiometry of n = 1. The heterocyclic scaffolds 1 and 2 were abolishing the binding of ATP into the binding pocket. They in-turn reduce the ability of FIKK9.1 kinase to phosphorylate its substrate. Our study found that compounds 1 and 2 are potent inhibitor of FIKK9.1 kinase and the inhibition of FIKK9.1 kinase using small molecules disturbs the parasite life cycle and leads to the death of parasites. This provides new insight in development of novel antimalarials.

The online version contains supplementary material available at 10.1007/s13205-023-03677-x.