Abstract
Sesquiterpene lactones are natural products of the Asteraceae family that have shown trypanocidal activity against Trypanosoma cruzi, even exceeding the effectiveness of drugs used in the treatment of American trypanosomiasis. However, there is no agreement on their mechanism of action and their specificity to interact with parasite proteins. For this reason, we aimed to find biological targets that can interact with these compounds by reverse virtual screening with ligand pharmacophores and putative binding sites and the use of bioinformatic databases. Therefore, 41 possible biological targets were found, and four of them (with crystallized proteins), interfering directly or indirectly in the trypanosomatid redox system, were studied in detail. As a first approach, we focused on the study of trypanothione reductase, and protein-ligand interaction fingerprint analyses were performed to find binding site determinants that promote a possible inhibition of the enzyme. This study contributes to the understanding of one of the putative mechanisms of action of sesquiterpene lactones on one of the numerous suggested targets.
Communicated by Ramaswamy H. Sarma
Author contributions
T.G.A: Investigation, Formal analysis, Writing original draft.
J.C: Methodology, Formal analysis, Writing, Reviewing & Editing. Molecular dynamics assesment.
A.B.C: Methodology, Formal analysis, Writing, Reviewing & Editing. Reverse screening assesment.
M.E.G: Resources, Project administration, Supervision, Writing, reviewing & editing.
V.E.N: Resources, Project administration, Supervision, Writing, reviewing & editing.
M.P: General conceptualization, Resources, Project administration, Supervision, Writing, reviewing & editing
Acknowledgments
T.G.A thanks CONICET for the fellowship granted to conduct his Ph.D. program. V.E.N and M.E.G. are members of the CONICET scientific career. M.P., J.C. and A.B.C. thank to PEDECIBA (Proyecto de Desarrollo de Ciencias Básicas), Comisión Sectorial de Investigación Científica (CSIC), Programa I+D, UdelaR (Universidad de la República) and Agencia de Investigación e Innovación (ANII, Proyecto ALIANZA.ALI.149574) for financial support. The authors are specially grateful to CONICET, UNC, and UdelaR for providing their facilities.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The authors declare that all the data supporting the findings of this study are included in the article and its supplementary information files.