Title:Structural Studies of Aminopeptidase P from Plasmodium falciparum: A Novel Target Against Malaria
Volume: 14
Issue: 3
Author(s): Polaboina Snigdha, Pachineella Lakshmana Rao, Nagu Prakash Prabhu and Insaf Ahmed Qureshi
Affiliation:
Keywords:
Malaria, Plasmodium falciparum, X-prolyl aminopeptidase, homology modelling, molecular dynamics simulation.
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.
