In silico Characterization of an Atypical MAPK Phosphatase of Plasmodium falciparum as a Suitable Target for Drug Discovery

Plasmodium falciparum , the causative agent of malaria, contributes to significant morbidity and mortality worldwide. Forward genetic analysis of the blood‐stage asexual cycle identified the putative phosphatase from PF 3D7_1305500 as an important element of intraerythrocytic development expressed throughout the life cycle. Our preliminary evaluation identified it as an atypical mitogen‐activated protein kinase phosphatase. Additional bioinformatic analysis delineated a conserved signature motif and three residues with potential importance to functional activity of the atypical dual‐specificity phosphatase domain. A homology model of the dual‐specificity phosphatase domain was developed for use in high‐throughput in silico screening of the available library of antimalarial compounds from Ch EMBL ‐ NTD . Seven compounds from this set with predicted affinity to the active site were tested against in vitro cultures, and three had reduced activity against a ∆ PF 3D7_1305500 parasite, suggesting PF 3D7_1305500 is a potential target of the selected compounds. Identification of these compounds provides a novel starting point for a structure‐based drug discovery strategy that moves us closer toward the discovery of new classes of clinical antimalarial drugs. These data suggest that mitogen‐activated protein kinase phosphatases represent a potentially new class of P . falciparum drug target.