Molecular Modeling, Virtual Screening, and Molecular Dynamics for Leishmania infantum Methionyl-tRNA Synthetase.
J Phys Chem B
; 126(51): 10834-10843, 2022 12 29.
Article
em En
| MEDLINE
| ID: mdl-36534784
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leishmania infantum
/
Leishmaniose Visceral
/
Metionina tRNA Ligase
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
J Phys Chem B
Assunto da revista:
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Estados Unidos