ABSTRACT
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 (Kd) 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. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03677-x.
ABSTRACT
AIM: The aim of the study is to investigate the galvanic corrosion potential of metal injection molding (MIM) brackets to that of conventional brackets under similar in vitro conditions with nickel-titanium and copper nickel-titanium archwires. MATERIALS AND METHODS: Twenty-five maxillary premolar MIM stainless steel brackets and 25 conventional stainless steel brackets and archwires, 0.16 inch, each 10 mm length, 25 nickeltitanium wires, 25 copper nickel-titanium wires were used. They were divided into four groups which had five samples each. Combination of MIM bracket with copper nickel-titanium wire, MIM bracket with nickel-titanium wire and conventional stainless steel brackets with copper nickel-titanium wire and conventional stainless steel brackets with nickel-titanium wires which later were suspended in 350 ml of 1 M lactic acid solution media. Galvanic corrosion potential of four groups were analyzed under similar in vitro conditions. Precorrosion and postcorrosion elemental composition of MIM and conventional stainless steel bracket by scanning electron microscope (SEM) with energy dispersive spectroscope (EDS) was done. RESULTS: MIM bracket showed decreased corrosion susceptibility than conventional bracket with copper nickeltitanium wire. Both MIM and conventional bracket showed similar corrosion resistance potential in association with nickel-titanium archwires. It seems that both brackets are more compatible with copper nickel-titanium archwires regarding the decrease in the consequences of galvanic reaction. The EDS analysis showed that the MIM brackets with copper nickel-titanium wires released less metal ions than conventional bracket with copper nickeltitanium wires. CONCLUSION: MIM brackets showed decreased corrosion susceptibility, copper nickel-titanium archwires are compatible with both the brackets than nickel-titanium archwires. CLINICAL SIGNIFICANCE: Clinically MIM and conventional brackets behaved more or less similarly in terms of corrosion resistance. In order to decrease the corrosion potential of MIM brackets, more precise manufacturing technique should be improved to get a more smoother surface finish.
