Structure based virtual screening identifies Pranlukast as a potential inhibitor against Plasmodium falciparum Adenosine Deaminase enzyme

Abstract

Malaria is a common infectious disease caused by Plasmodium species and the most lethal malarial parasite is P. falciparum. Considering the high malaria mortality rate and rapid emergence of multi drug resistant strains of malarial parasites necessitates the development of novel drugs. In this work, Adenosine Deaminase (ADA), the first enzyme of the purine salvage pathway was selected as a drug target due to its significant role in nucleic acid biosynthesis. Since the experimental structure of P. falciparum ADA is not available in Protein Data Bank (PDB), the target protein was modeled using comparative homology modeling approach. The overall quality of the model was good in terms of backbone dihedral angles distribution, ERRAT values, Profiles 3D score, knowledge based energy score and Z-score. The physico-chemical properties, secondary elements and active site pockets were analyzed using various in silico tools. Drug-like compounds retrieved from PubChem database was subjected to molecular docking with ADA. Pranlukast, the promising lead identified shows comparatively lower binding free energy compared to the control (5′-Methylthiocoformycin) and interacts with ADA through two hydrogen bonds as well as hydrophobic interactions. The molecular dynamics (MD) simulation studies revealed that Pranlukast binding does not have major alteration in the compactness and mobility of the protein backbone structure but it has an influence in the folding pattern and intramolecular hydrogen bonds formation. Thus, Pranlukast seems to be a potential inhibitor against P. falciparum ADA, which needs further validation by in vitro or in vivo experimental studies.