Structural studies of aminopeptidase P from Plasmodium falciparum: A novel target against malaria

Abstract

Background: Decreased efficiency of artemisinin combination therapy (ACT) and the declining efficacy of affordable drugs for malaria is a major concern with half of the world population living in countries endemic to the disease; hence the development of the next generation anti-malarial drugs is the need of the hour. Objective: The present study is the first attempt to characterize the three dimensional structure of Plasmodium falciparum X-prolyl aminopeptidase (PfAPP), a newly detected target for malaria treatment. Method: The three dimensional structure of the protein had been modelled and validated using different tools. Also, the stability of the model was analyzed by molecular dynamics simulation (MDS) studies. The MDS studies involving trajectory based analysis of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of the system revealed stability of the system throughout the dynamics, the model was used for prediction of ligand-binding site of the protein. Results: Comparative sequence and structural analysis of the model with the template (human homologue APP1) revealed the conservation of two of the five active site residues and functionally important secondary shell residues surrounding the active site, suggesting the possibility of conserved catalytic mechanism in the malarial X-prolyl aminopeptidase. In the absence of the experimental crystal structure of PfAPP, the proposed model could serve as a basis for ligand docking prediction and elucidation of its catalytic mechanism that might be useful for the development of new inhibitors accounting for the rational structure-based drug design of the efficient next generation anti-malarial therapeutics.