Design of Inhibitors for Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Enzyme of Leishmania mexicana

Author(s): Krisnna M.A. Alves, Fábio José Bonfim Cardoso, Kathia M. Honorio, Fábio A. de Molfetta*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 6 , 2020

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Graphical Abstract:


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 available.

Keywords: Leishmaniosis, glyceraldehydes-3-phosphate dehydrogenase, pharmacophore analysis, molecular docking, molecular dynamics, Leishmania genus.

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Year: 2020
Published on: 07 September, 2020
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DOI: 10.2174/1573406415666190712111139
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