Molecular Modeling, Virtual Screening, and Molecular Dynamics for <i>Leishmania infantum</i> Methionyl-tRNA Synthetase.

Teles, Henrique R; Valli, Marilia; Ferreira, Leonardo L G; Andricopulo, Adriano D

Molecular Modeling, Virtual Screening, and Molecular Dynamics for Leishmania infantum Methionyl-tRNA Synthetase.

Teles, Henrique R; Valli, Marilia; Ferreira, Leonardo L G; Andricopulo, Adriano D.

Afiliação

Teles HR; Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of São Carlos, University of São Paulo (USP), Av. João Dagnone, no. 1100, São Carlos, SP 13563-120, Brazil.
Valli M; Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of São Carlos, University of São Paulo (USP), Av. João Dagnone, no. 1100, São Carlos, SP 13563-120, Brazil.
Ferreira LLG; Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of São Carlos, University of São Paulo (USP), Av. João Dagnone, no. 1100, São Carlos, SP 13563-120, Brazil.
Andricopulo AD; Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of São Carlos, University of São Paulo (USP), Av. João Dagnone, no. 1100, São Carlos, SP 13563-120, Brazil.

J Phys Chem B ; 126(51): 10834-10843, 2022 12 29.

Article em En | MEDLINE | ID: mdl-36534784

RESUMO

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.

Assuntos

Leishmania infantum; Leishmaniose Visceral; Metionina tRNA Ligase; Humanos; Simulação de Dinâmica Molecular; Leishmaniose Visceral/tratamento farmacológico; Simulação de Acoplamento Molecular

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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

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