Homology modeling, docking and molecular dynamics of the Leishmania mexicana arginase: A description of the catalytic site useful for drug design

The crystallographic structure of the Leishmania mexicana arginase, an attractive target for the design of leishmanicidal agents, is still unknown. For this reason, we report a computer-assisted homology study conducted to build its three-dimensional structure based on the known sequence of amino acids of this enzyme. In this study, the amino acid sequence in the arginase of the parasite was compared with the sequence of the amino acids in the crystallographic structure of rat and human liver arginases. The best similarity was found with the rat liver arginase. The catalytic site of the three-dimensional arginase structure built for L. mexicana has important structural differences as compared with that of the human liver arginase with regard to reasonable design selective compounds against L. mexicana. With this information, a docking study was conducted to find the inhibitors of this enzyme. 1439 molecules were docked and 18 were selective to the L. mexicana arginase. Moreover, molecular dynamics were carried out to study the stability of the homologue protein (including manganeses) and the ligand–enzyme complex. The results indicated that the manganese remains inside the protein throughout the simulation. Besides, hydrogen bonds interactions between the ligand and the arginase were analyzed. These results provide important information for the design of new inhibitors.

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► L. mexicana arginase is involved in the energy generation and defense of the parasite.
► A 3D structure of this enzyme is described for the first time.
► Differences in L. mexicana arginase are useful for the design of selective ligands.
► Docking studies led to 18 highly selective benzimidazole derivatives.
► Molecular dynamics indicated that the enzyme and ligand–enzyme complex are stable.