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Título

Identification of L. infantum trypanothione synthetase inhibitors with leishmanicidal activity from a (non-biased) in-house chemical library

AutorAlcón-Calderón, Mercedes; Lucio, Héctor de; García-Soriano, Juan Carlos; Revuelto, Alejandro CSIC ORCID; Castro, Sonia de CSIC ORCID; López-Gutiérrez, Celia; San-Félix, Ana CSIC ORCID ; Quesada, Ernesto CSIC ORCID ; Gago, Federico CSIC ORCID; Camarasa Rius, María José CSIC ORCID; Jiménez-Ruiz, Antonio; Velázquez, Sonsoles CSIC ORCID CVN
Palabras claveTrypanothione synthetase
Leishmania infantum
Competitive and non-competitive inhibitors
Molecular docking
Molecular dynamics
Fecha de publicación2022
EditorElsevier
CitaciónEuropean Journal of Medicinal Chemistry 243 : 114675 (2022)
ResumenRedox homeostasis in trypanosomatids is based on the low-molecular-weight trypanothione, an essential dithiol molecule that is synthetized by trypanothione synthetase (TryS) and maintained in its reduced state by trypa- nothione disulfide reductase (TryR). The fact that both enzymes are indispensable for parasite survival and absent in the mammalian hosts makes them ideal drug targets against leishmaniasis. Although many efforts have been directed to developing TryR inhibitors, much less attention has been focused on TryS. The screening of an in-house library of 144 diverse molecules using two parallel biochemical assays allowed us to detect 13 inhibitors of L. infantum TryS. Compounds 1 and 3 were characterized as competitive inhibitors with Ki values in the low micromolar range and plausible binding modes for them were identified by automated ligand docking against refined protein structures obtained through computational simulation of an entire catalytic cycle. The proposed binding site for both inhibitors overlaps the polyamine site in the enzyme and, additionally, 1 also occupies part of the ATP site. Compound 4 behaves as a mixed hyperbolic inhibitor with a Ki of 0.8 μM. The activity of 5 is clearly dependent on the concentration of the polyamine substrate, but its kinetic behavior is clearly not compatible with a competitive mode of inhibition. Analysis of the activity of the six best inhibitors against intracellular amastigotes identified 5 as the most potent leishmanicidal candidate, with an EC50 value of 0.6 μM and a selectivity index of 35.
Versión del editorhttps://doi.org/10.1016/j.ejmech.2022.114675
URIhttp://hdl.handle.net/10261/279364
DOI10.1016/j.ejmech.2022.114675
ISSN0223-523
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