Background: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3-
phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease.
Objective: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in
Leishmania mexicana (L. mexicana).
Methods: A search for novel antileishmanial molecules was carried out based on similarities from
the pharmacophoric point of view related to the binding site of the crystallographic enzyme using
the ZINCPharmer server. The molecules selected in this screening were subjected to molecular
docking and molecular dynamics simulations.
Results: Consensual analysis of the docking energy values was performed, resulting in the selection
of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze
the main interactions and subjected to toxicophoric evaluation, culminating in the selection of
three compounds, which were subsequently submitted to molecular dynamics simulations. The
docking results showed that the selected compounds interacted with GAPDH from L. mexicana,
especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results
obtained from molecular dynamics, it was observed that one of the loop regions, corresponding
to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting
in the positioning and the molecular recognition via residues responsible for the catalytic activity.
Conclusion: The use of molecular modeling techniques enabled the identification of promising
compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here
can serve as a starting point to design new and more effective compounds than those currently