Virtual Screening, Molecular Modelling and Biochemical Studies to Exploit PF14_0660 as a Target to Identify Novel Anti-malarials

Vimee      Raturi; Kumar      Abhishek; Subhashis      Jana; Subhendu   Sekhar   Bag; Vishal      Trivedi

Abstract

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.

Keywords: Plasmodium falciparum, phosphatase activity, molecular modelling, virtual screening, anti-malarials, tyrosine phosphatase.

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Graphical Abstract

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DOI https://dx.doi.org/10.2174/1570180815666180727121200	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

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Virtual Screening, Molecular Modelling and Biochemical Studies to Exploit PF14_0660 as a Target to Identify Novel Anti-malarials

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