Background: Plasmodium falciparum leucyl aminopeptidase (PfA-M17) regulates the intracellular
pool of amino acids required for the growth and development of parasites. Thus, PfA-M17 is a
promising target for anti-malarial drug development.
Method: In the present study, structure-based drug design was used to identify novel PfA-M17 inhibitors,
which were subsequently validated by in vitro PfA-M17 and human LAP3 enzyme inhibition assay.
A library of 3,147,882 compounds was screened using receptor-based virtual screening against the
active site of PfA-M17, and three levels of accuracy were used: high-throughput virtual screening, gridbased
ligand docking with energetics (Glide standard precision) and Glide extra precision.
Results: Seventeen screened compounds were selected and tested in the rPfA-M17 enzyme inhibition
assay. Of these nine compounds were found to be effective inhibitors. To test the target activity, all nine
PfA-M17 inhibitors were tested against rhLAP3, the human homolog of PfA-M17. One compound
(compound 2) was found to be moderately effective against PfA-M17 (Ki = 287 μM) with limited inhibitory
activity against hLAP3 (Ki of 4,464 μM). Subsequently, induced fit docking and pharmacophore
modelling were used to further understand more precise ligand–protein interactions in the protein–inhibitor complexes.
Conclusion: Among the 9 effective PfA-M17 inhibitors, 5 compounds were found effective in the P.
falciparum schizont maturation inhibition (SMI) assay. A good correlation (r =0.83) was observed between
the rPfA-M17 enzyme inhibition concentration and SMI assay.