Identification of Plasmodium Protein Casein Kinase 2 (PfCK2) inhibitors for malarial treatment Daniel Moscoh Ayine-Tora 1 , Jerry Joe E.K. Harrison 1 , Yaw Aniweh 2 1 Department of Chemistry,University of Ghana, Ghana, 2 West African Center for Cell Biology of Infectious Pathogens, University of Ghana, Ghana In 2021, there were about 247 million malaria cases with 619 thousand deaths globally. 593 thousand of this death was recorded in WHO African Region. Plasmodium falciparum and Plasmodium vivax protozoan parasites is responsible for most of the virulent forms of this disease. The is emergence of parasite resistance to most of the available antimalarial treatments, including artemisinins. 1 Therefore, development of new inhibitors against less targeted receptors such as PfCK2 is urgently needed. PfCK2 has been shown to be essential for both asexual and gametocyte development. 2 PfCK2 plays a broad regulatory role like that of the mammalian orthologue. This is supported by the wide localization of PfCK2 in both the cytoplasm and nucleus of the parasite. 3,4 Virtual high throughput screening in conjunction with In vitro susceptibility assays have been used to predict PfCK2 inhibitors. Molecular modelling shows that, the active ligands form hydrogen bonds with Tyr54, Lys53, Ser179, Ile120, Glu118. Some of the hits shows single digit µM IC 50 values. The discovery of PfCK2 inhibitor as a multi-staged drug candidate will enhance malarial therapy. A B
Figure. 1 The docked configuration of 1 at the site of PfCK2 using ChemPLP configuration. The protein surface is rendered. The ligand occupies the binding pocket. Blue depicts hydrophilic region on the surface, brown depicts hydrophobic region and grey shows neutral region. (B) Hydrogen bonds are shown as green lines between 46784 and the amino acids Tyr54,119, Glu118, Ile120, Ser179, Lys53 and π bond is form between 46784 and Met167 References 1. World Malaria Report 2022. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022.Pease, B.N.; Huttlin, E.L.; Jedrychowski, M. P.; Talevich, E., Global analysis of protein expression and phosphorylation of three stages of Plasmodium falciparum intraerythrocytic development. Proteome Res. 2013, 12 . 2. Holland, Z., Prudent, R., Reiser, J. B., Cochet, C. & Doerig, C. Functional analysis of protein kinase CK2 of the human malaria parasite Plasmodium falciparum . EukaryoticCell. 2009, 8 . 3. Dastidar, E. G.; Dayer G.; Holland, Z. M.; Dorin-Semblat, D.; Claes, A; Chêne A., Involvement of Plasmodium falciparum protein kinase CK2 in the chromatin assembly BMC Biology. 2012, 10 .
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