Design of new compounds for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) enzyme of leishmania mexicana from molecular modeling

Abstract

Leishmaniosis is a disease caused by protozoans of the Leishmania genus, which is an endemic disease in more than 98 countries. Besides, leishmaniosis is among the so-called neglected tropical diseases, with little interest of clinical researches, there is no vaccine and therapeutic arsenal is very inadequate. The glycolytic pathway of protozoa responsible for the disease has been investigated as an attractive molecular target for design new drugs, and one of the enzymes that have aroused interest is the glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Thus, the objective of this work was to find possible inhibitors for the GAPDH enzyme from Leishmania mexicana (L. mexicana) in order to improve the complementarity of lead compound. The search was made on PubChem, ZINC and SciFinder databases, and all analogues were then subjected to toxicity prediction. The docking calculations results with GAPDH enzyme showed important hydrogen bonds with the residues of amino acids Arg249, Ser224, Ser226, Thr167 and Thr226, showing the same interactions obtained in the literature data. Also, molecular docking of all these compounds was checked against human GAPDH enzyme, to minimize adverse reactions. From this, we selected the most promising ligand to Molecular Dynamics (MD) simulations, and, subsequently, the Root Mean Square Deviation (RMSD) values showed that system was stable and the value of binding free energy was favorable. Thus, the results obtained in this study to selected compound can be used to design new candidates to inhibitors of the GAPDH enzyme from L. mexicana.