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

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:

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

Acknowledgments

RP acknowledges University Grants Commission (UGC), India for Senior Research Fellowship (SRF). PG acknowledges Council for Scientific and Industrial Research (CSIR), India for SRF. RK acknowledges Department of Biotechnology (DBT), India for SRF.