posted on 2022-12-19, 20:06authored byHenrique
R. Teles, Marilia Valli, Leonardo L.G. Ferreira, Adriano D. Andricopulo
Visceral leishmaniasis is a neglected tropical disease
(NTD) caused
by Leishmania infantum and L. donovani that is lethal in cases of nontreatment. The treatments are limited
by serious drawbacks involving safety, resistance, stability, and
high costs. In this work, we aimed to identify inhibitors of Leishmania infantum methionyl-tRNA synthetase (LiMetRS), a validated molecular target for leishmaniasis drug discovery,
using a combination of strategies. A virtual database of compounds
was organized by filtering compounds from the ZINC15 database. Homology
modeling was used to obtain the structure of LiMetRS
based on the crystal coordinates of the enzyme from Trypanosoma
brucei (TbMetRS). A virtual screening using
molecular docking identified 10 candidate compounds from among more
than 5 million that were included in the initial database. The selected
hits were further evaluated using a script created in this work to
select only the ligands that interacted with specific amino acids
in the catalytic site of the enzyme. Furthermore, suitable pharmacokinetic
profiles were predicted for the selected compounds, especially a good
balance between aqueous solubility and lipophilic character, no ability
to cross the blood–brain barrier, good oral absorption, and
no liability toward P-gp efflux for most compounds. Six compounds
were then subjected to all-atom molecular dynamics. Two compounds
showed good stability when bound to the leishmanial enzyme, which
provided a deeper understanding of the structural differences between TbMetRS and LiMetRS that can guide further
drug discovery efforts for visceral leishmaniasis.