In Silico Characterization of an Atypical MAPK Phosphatase of Plasmodium Falciparum as a Suitable Target for Drug Discovery

Campbell, Christopher
Santiago, Daniel N.
Guida, Wayne C.
Manetsch, Roman
Adams, John H.
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Chemical Biology and Drug Design
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 PF3D7_1305500 as an important element of intraerythrocytic development expressed throughout the life cycle. Our preliminary evaluation identified it as an atypical MAPK phosphatase. Additional bioinformatics analysis delineated a conserved signature motif and three residues with potential importance to functional activity of the atypical dual-specificity phosphatase (DUSP) domain. A homology model of the DUSP domain was developed for use in high-throughput in silico screening of the available library of antimalarial compounds from ChEMBL-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 ΔPF3D7_1305500 parasite, suggesting PF3D7_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 towards the discovery of new classes of clinical antimalarial drugs. These data suggest that MAPK phosphatases represent a potentially new class of P. falciparum drug target.
Campbell, C. O., Santiago, D. N., Guida, W. C., Manetsch, R., & Adams, J. H. (2014). In silico characterization of an atypical MAPK phosphatase of plasmodium falciparum as a suitable target for drug discovery. Chemical Biology & Drug Design, 84, 158–168.