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J Biomol Struct Dyn. 2017 Nov 6:1-10. doi: 10.1080/07391102.2017.1392365. [Epub ahead of print]

High throughput in silico identification and characterization of Plasmodium falciparum PRL phosphatase inhibitors.

Author information

1
a Translational Bioinformatics Group , International Centre for Genetic Engineering and Biotechnology , Aruna Asaf Ali Marg, New Delhi - 110067 , India.
2
b Malaria Biology Group , International Centre for Genetic Engineering and Biotechnology , Aruna Asaf Ali Marg, New Delhi - 110067 , India.
3
c Parasite Cell Biology Group , International Centre for Genetic Engineering and Biotechnology , Aruna Asaf Ali Marg, New Delhi - 110067 , India.
4
d Centre for Genetics and Genomics, School of Life Sciences , Queens Medical Centre, University of Nottingham , Nottingham NG2 7UH , UK.

Abstract

Kinases and phosphatases are involved in many essential processes in Plasmodium lifecycle. Among the identified 67 Plasmodium falciparum phosphatases, Phosphatase of Regenerating Liver (PRL) family protein homolog, PfPRL, is an essential parasite tyrosine phosphatase. PfPRL is shown to be prenylated, secreted, and involved in the host invasion process. In the present study, a structure-based high throughput in silico screening of PfPRL binders, using ChEMBL-NTD compounds lead to the identification of nine compounds based on binding energy, Lipinski rule of five, and QED score. The most of the shortlisted compounds are known to inhibit parasite growth at a concentration (EC50) ≤2 μm in in vitro P. falciparum culture assays. MD simulations were carried out on the shortlisted nine potential enzyme-inhibitor complexes to analyze specificity, stability, and to calculate the free binding energies of the complexes. The study identifies PfPRL as one of the potential drug targets for selected ChEMBL-NTD compounds that may be exploited as a scaffold to develop novel antimalarials.

KEYWORDS:

in silico drug screening; kinases; ligand clustering; molecular dynamics; phosphatases; post-translational modifications

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