In silico identification of α-bisabolol and letestuianin C as potential inhibitors of Trypanosoma brucei trypanothione reductase

Abstract

Despite the recent advances in drug research, finding a safe, effective, and easy to use chemotherapy for human African trypanosomiasis (HAT) remains a challenging task. Trypanosomatids have developed resistance mechanisms towards melarsoprol (the current drug of choice), and the fact that it is poisonous is problematic. Therefore, a search for alternative therapeutics against the parasite is urgently needed. Natural products offer potential for drug discovery, but little or nothing is known about the target of inhibition or possible mode of inhibition. Therefore, this study aimed to use molecular docking and molecular dynamics simulations to evaluate 30 antitrypanosomal natural products as potential inhibitors of trypanothione reductase, a key protein necessary for the survival of the Trypanosoma brucei. The study also assessed the pharmacokinetic properties of the most promising compounds. Of the compounds evaluated, α-bisabolol, letestuianin C, waltherione, and mexicanin E were found to bind at the active site of TR and interact with Met115, Tyr112, and Trp23, which are essential for enzyme functioning. Molecular dynamic simulations revealed the sustained binding of α-bisabolol and letestuianin C throughout the simulation period, potentially obstructing the binding of the substrate (T[S]₂) and impeding catalysis. The binding of these compounds to TR led to the presence of solvent molecules in the enzyme’s active site, and this could potentially lead to protein aggregation. Furthermore, α-bisabolol and letestuianin C exhibited promising safety profiles. Consequently, α-bisabolol and letestuianin C have been shown to be viable candidates for targeting trypanothione reductase in the fight against human African trypanosomiasis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human African trypanosomiasis (HAT)
• neglected tropical diseases (NTDs)
• molecular docking
• molecular dynamics simulations
• antitrypanosomal natural products
• trypanosomatids

Acknowledgements

We would like to acknowledge the Center for High Performance Computing in Cape Town, South Africa for providing us with unrestricted access to the Lengau cluster, which was instrumental in conducting the MD simulations.

Author contributions

LSB, JOM, PBN and ENG conceived the study. All experiments were designed by LSB, PBN, JOM and ENG. Computations were made by JOM and PBN. Data analysis was by JOM, ENG, PBN and LSB. Manuscript was prepared by PBN, JOM, ENG and LSB. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Additional information

Funding

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