Prospecção virtual e dinâmica molecular de potenciais ligantes para a inibição da proteína Tripanotiona Redutase de Leishmania infantum

Abstract

Leishmaniasis is a neglected tropical disease, caused by protozoa of the genus Leishmania spp, has visceral leishmaniasis (VL) as its most severe form, caused by Leishmania infantum (LI). The enzyme trypanothione reductase (TR) is a promising molecular target for inhibitors due to its role in the redox homeostasis of the parasite and its absence in the human host. TR enables the conversion of tripanothione dithiol using the co-substrate NADPH, which is essential for the pathogen's antioxidant metabolism. This project used drug design tools to identify potential TR inhibitors in LI. The structural model of TR was initially obtained from the Protein Data Bank (PDB id: 6ER5). Other structures of potential inhibitors were also identified in the PDB. Shape-based models were generated from the interaction interface between the enzyme and the ligands using vROCs programs. The 500 compounds with the best prospecting score from each library (including NuBBE, FDA, ZINC12, CL, and EXP) were subjected to molecular docking with TR using the GOLD program. The pharmacokinetic properties (ADME-T) of the 10 best compounds were predicted by the pkCSM server. Among the 10 best molecules, 2 proceeded to the molecular dynamics (MD) stage, a method that consists of evaluating protein-ligand interactions over time and analyzing possible conformations using the following methods: Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), number of hydrogen bonds, and bond energy analysis. Among the most prominent ligands, NuBBE 1208 and NuBBE 877 showed the highest inhibitory potential against LI TR. The results show that the Drug Design approach can identify promising compounds for TR inhibition, highlighting the potential of NuBBE 1208 and NuBBE 877. In addition, they suggest new avenues for the development of therapies against visceral leishmaniasis, which may have a significant impact on the production of new drugs and the fight against this disease.