Background:
Malaria Parasite relies heavily on signal transduction pathways to control
growth, the progression of the life cycle and sustaining stress for its survival. Unlike kinases,
Plasmodium's phosphatome is one of the smallest and least explored for identifying drug target
for clinical intervention. PF14_0660 is a putative protein present on the chromosome 14 of
Plasmodium falciparum genome.
Methods:
Multiple sequence alignment of PF14_0660 with other known protein phosphatase indicate
the presence of phosphatase motif with specific residues essential for metal binding, catalysis
and providing structural stability. PF14_0660 is a mixed α/β type of protein with several β -sheet
and α-helix arranged to form βαβαβα sub-structure. The surface properties of PF14_0660 is conserved
with another phosphate of this family, but it profoundly diverges from the host protein tyrosine
phosphatase. PF14_0660 was cloned, over-expressed and protein is exhibiting phosphatase
activity in a dose-dependent manner. Docking of Heterocyclic compounds from chemical libraries
into the PF14_0660 active site found nice fitting of several candidate molecules.
Results:
Compound PPinh6, PPinh 7 and PPinh 5 are exhibiting antimalarial activity with an IC50
of 1.4 ± 0.2µM, 3.8 ± 0.3 µM and 9.4 ± 0.6µM respectively. Compound PPinh 6 and PPinh 7 are
inhibiting intracellular PF14_0660 phosphatase activity and killing parasite through the generation
of reactive oxygen species.
Conclusion:
Hence, a combination of molecular modelling, virtual screening and biochemical study
allowed us to explore the potentials of PF14_0660 as a drug target to design anti-malarials.
Materials and Molecular Modelling at the Exascale
