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

2019 ◽  
Vol 16 (4) ◽  
pp. 417-426
Author(s):  
Vimee Raturi ◽  
Kumar Abhishek ◽  
Subhashis Jana ◽  
Subhendu Sekhar Bag ◽  
Vishal Trivedi
Keyword(s):  
Virtual Screening ◽  
Phosphatase Activity ◽  
Molecular Modelling ◽  
Drug Target ◽  
Antimalarial Activity ◽  
Biochemical Study ◽  
Tyrosine Phosphatase ◽  
Host Protein ◽  
Dependent Manner ◽  
Multiple Sequence

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 ± 0.6&#181M 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.

scholarly journals Antibodies to protein tyrosine phosphatase receptor type O (PTPro) increase glomerular albumin permeability (Palb)

2009 ◽  
Vol 297 (1) ◽  
pp. F138-F144 ◽  
Author(s):  
Deane S. Charba ◽  
Roger C. Wiggins ◽  
Meera Goyal ◽  
Bryan L. Wharram ◽  
Jocelyn E. Wiggins ◽  
...  
Keyword(s):  
Phosphatase Activity ◽  
Protein Tyrosine Phosphatase ◽  
Polyclonal Antibodies ◽  
Transmembrane Protein ◽  
Tyrosine Phosphatase ◽  
Apical Surface ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Protein Tyrosine ◽  
Filtration Barrier

Glomerular capillary filtration barrier characteristics are determined in part by the slit-pore junctions of glomerular podocytes. Protein tyrosine phosphatase receptor-O (PTPro) is a transmembrane protein expressed on the apical surface of podocyte foot processes. Tyrosine phosphorylation of podocyte proteins including nephrin may control the filtration barrier. To determine whether PTPro activity is required to maintain glomerular macromolecular permeability, albumin permeability ( Palb) was studied after incubation of glomeruli from normal animals with a series of monoclonal (mAb) and polyclonal antibodies. Reagents included mAbs to rabbit and rat PTPro and polyclonal rabbit immune IgG to rat PTPro. mAb 4C3, specific to the amino acid core of PTPro, decreased its phosphatase activity and increased Palb of rabbit glomeruli in a time- and concentration-dependent manner. In contrast, mAb P8E7 did not diminish phosphatase activity and did not alter Palb. Preincubation of 4C3 with PTPro extracellular domain fusion protein blocked glomerular binding and abolished permeability activity. In parallel experiments, Palb of rat glomeruli was increased by two mAbs (1B4 and 1D1) or by polyclonal anti-rat PTPro. We conclude that PTPro interaction with specific antibodies acutely increases Palb. The identity of the normal ligand for PTPro and of its substrate, as well as the mechanism by which phosphatase activity of this receptor affects the filtration barrier, remain to be determined.

Virtual Screening Techniques to Probe the Antimalarial Activity of some Traditionally Used Phytochemicals

2016 ◽  
Vol 19 (7) ◽  
pp. 572-591 ◽  
Author(s):  
Indira G. Shibi ◽  
Lilly Aswathy ◽  
Radhakrishnan S. Jisha ◽  
Vijay H. Masand ◽  
Jayant M. Gajbhiye
Keyword(s):  
Virtual Screening ◽  
Antimalarial Activity ◽  
Screening Techniques

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

scholarly journals A screen of FDA-approved drugs identifies inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dylan R. Rivas ◽  
Mark Vincent C. Dela Cerna ◽  
Caroline N. Smith ◽  
Shilpa Sampathi ◽  
Blaine G. Patty ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Allosteric Site ◽  
Human Embryonic Kidney Cells ◽  
Protein Tyrosine ◽  
Tumor Cell Migration ◽  
Colorectal Cancer Cells ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractProtein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

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