Beyond traditional medications: exploring novel and potential inhibitors of trypanothione reductase (LmTr) of Leishmania parasites

Abstract

The trypanothione reductase enzyme, which neutralizes the reactive oxygen species produced inside the macrophages to kill the parasites, is one of the evasion strategies Leishmania uses to survive inside the cells. The vitality of the parasite depends on Leishmania major trypanothione reductase (LmTr), a NADPH-dependent flavoprotein oxidoreductase essential for thiol metabolism. Since this enzyme is distinct and lacking in humans, we focused on it in our study to screen for new inhibitors to combat leishmaniasis. Using the I-TASSER server, a three-dimensional model of LmTr was generated. The Autodock vina program was used in high-throughput virtual screening of the ZINC database. The top seven molecules were ranked according to their binding affinity. The compounds with the highest binding affinities and the right number of hydrogen bonds were chosen. These compounds may be effective at inhibiting the target enzyme’s (LmTr) activity, making them new leishmaniasis treatments. These compounds may serve as a useful starting point for a hit-to-lead approach in the quest for new anti-Leishmania drugs that are more efficient and less cytotoxic. The average node degree is 5.09, the average local clustering coefficient is 0.868, and the PPI enrichment p-value is 8.9e-06, indicating that it is sufficiently connected to regulate the network. TRYR (LmTr protein) also interacts physically with ten additional proteins in the pathogenesis network. The findings of the study indicated that successfully suppressing the LmTr protein in vitro and in vivo may finally result in regulating the L. major pathogenesis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Leishmaniasis
• trypanothione reductase
• evasion strategies
• virtual screening
• inhibitors
• leishmania major
• hit-to-lead approach

Acknowledgment

The authors extend their appreciation to the Deanship of Scientific Research at Northern Border University, Arar, KSA, for funding this research work through the project number “NBU-FFR-2023-0156.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author’s contributions

Conception, M.S., M.A.B., and M.I.; Study Design, M.S., M.A.B., M.S.A., M.A., A.R.A., L.E., S.M.B.A., F.F.A.A., A., and M.I.; Execution, M.S., M.A.B., M.S.A., and M.I.; Acquisition of data, M.S., M.A.B., M.S.A., and M.A.; analysis and interpretation, M.S., M.A.B., M.S.A., M.A., A.R.A., L.E., S.M.B.A., F.F.A.A., A., and M.I.; Writing—original draft, M.S., M.A.B and M.I.; Writing—review & editing, M.S., M.A.B., M.S.A., M.A., A.R.A., L.E., S.M.B.A., F.F.A.A., A., and M.I.; All authors reviewed the final version of the manuscript and consented to submission to the Journal of Biomolecular Structure and Dynamics. All authors agree to take responsibility and are accountable for the contents of the article. All authors share responsibility to resolve any questions raised about the accuracy or integrity of the published work.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.