title: In silico characterization of an atypical MAPK phosphatase of Plasmodium falciparum as a suitable target for drug discovery.
abstract: 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 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 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 ∆PF3D7_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 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.
authors.affiliation: Department of Global Health, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Christopher O
authors.initials: CO
authors.lastname: Campbell
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Santiago
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Guida
authors.forename: Roman
authors.initials: R
authors.lastname: Manetsch
authors.forename: John H
authors.initials: JH
authors.lastname: Adams
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D000962:Antimalarials; D054638:Dual Specificity Phosphatase 1
keywords: chemical structure; drug discovery; functional genomics (gene KO/KI); kinase; malaria; phosphatase; protein structure