In silico characterization of an atypical MAPK phosphatase of Plasmodium falciparum as a suitable target for drug discovery

Chem Biol Drug Des. 2014 Aug;84(2):158-68. doi: 10.1111/cbdd.12315. Epub 2014 May 12.


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.

Keywords: chemical structure; drug discovery; functional genomics (gene KO/KI); kinase; malaria; phosphatase; protein structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antimalarials / chemistry*
  • Antimalarials / pharmacology*
  • Drug Discovery
  • Dual Specificity Phosphatase 1 / antagonists & inhibitors*
  • Dual Specificity Phosphatase 1 / chemistry
  • Dual Specificity Phosphatase 1 / genetics
  • Dual Specificity Phosphatase 1 / metabolism
  • Humans
  • Malaria, Falciparum / drug therapy
  • Models, Molecular
  • Molecular Sequence Data
  • Phylogeny
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Plasmodium falciparum / genetics
  • Sequence Alignment


  • Antimalarials
  • Dual Specificity Phosphatase 1