Identification of potential biological target for trypanocidal sesquiterpene lactones derivatives

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

Keywords:

• Sesquiterpene lactones
• trypanosomatidae
• molecular dynamics
• reverse virtual screening
• Ambrosia tenuifolia
• Asteraceae

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.

Additional information

Funding

This work has been funded by CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) under Grant (PIP 2015-2017. N° 11220150100208), ANPCYT (Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación) under Grant (PICT 2016-2015), SeCyT-UNC (Universidad Nacional de Córdoba) under Grant (2018-2019 33820180100152CB), ONR Global (Office of Naval Research, USA) under Grant (N62909-21-1-2052), 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).