The Amaryllidaceae alkaloid, montanine, is a potential inhibitor of the Trypanosoma cruzi trans-sialidase enzyme

Abstract

Trypanosoma cruzi is the parasite that causes the chronic malady known as Chagas disease (CD). Only nifurtimox and benznidazole are currently approved to treat CD in acute and chronic phases. To minimize the danger of disease transmission and as a therapy, new compounds that are safer and more effective are required. It has been demonstrated that Amaryllidaceae plants suppress the growth of T. cruzi – the causative agent of CD. However, little research has been done on their potential protein targets in the parasite. In this study, an in-silico approach was used to investigate the interactions of the Amaryllidaceae alkaloids with trans-sialidase, a confirmed protein target of T. cruzi. The nature and efficiency of the main binding modes of the alkaloids were investigated by molecular docking. Trans-sialidase active site residues were bound by the alkaloids with binding energies varying from −8.9 to −6.9 kcal/mol. From the molecular docking investigation, all the alkaloids had strong interactions with the crucial amino acid residues (Glu230, Tyr342, and Asp59) required for trans-sialidase catalysis. Montanine was the most stable compound throughout the molecular dynamics simulation and had a favorable docking binding energy (−8.9 kcal/mol). The binding free energy (MM-GBSA) of the montanine complex was −14.6 kcal/mol. The pharmacokinetic properties investigated demonstrated that all the evaluated compounds exhibit suitable oral administration requirements. Overall, this in silico study suggests that the Amaryllidaceae alkaloids could potentially act as inhibitors of trans-sialidase.

Communicated by Ramaswamy H. Sarma

Keywords:

• Chagas disease
• montanine
• hippeastrine
• molecular docking and molecular dynamics simulation
• American trypanosomiasis
• neglected tropical diseases

Acknowledgment

The authors are grateful to the Center for High-Performance Computing, Cape Town, South Africa which granted generous access to the Lengau cluster for the MD simulations.

Author contributions

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

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

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

Additional information

Funding

No direct funding for this study was received.