Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity

Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm. In Plasmodium, it is suggested that these protein kinases are essential for both asexual and sexual blood-stage parasites, reinforcing their potential as targets for multi-stage antimalarials. To identify new putative PfCK2 alpha inhibitors, we utilized an in silico chemogenomic strategy involving virtual screening with docking simulations and quantitative structure-activity relationship predictions. Our investigation resulted in the discovery of a new quinazoline molecule (542), which exhibited potent activity against asexual blood stages and a high selectivity index (>100). Subsequently, we conducted chemical-genetic interaction analysis on yeasts with mutations in casein kinases. Our chemical-genetic interaction results are consistent with the hypothesis that 542 inhibits yeast Cka1, which has a hinge region with high similarity to PfCK2 alpha. This finding is in agreement with our in silico results suggesting that 542 inhibits PfCK2 alpha via hinge region interaction.

Automated summary

Drug resistance is a major challenge in malaria control, and this study discovered a new potential antimalarial compound through computational chemistry methods. The compound showed strong activity against asexual blood-stage parasites. Furthermore, the study found that the compound inhibited specific protein kinases in yeast through chemical-genetic interaction analysis. These findings suggest that the compound has the potential to be a drug target for multi-stage antimalarials.