Abstract 2266 Amaryllidaceae Alkaloids as Potential Inhibitors of the Trypanosoma cruzi Trans-sialidase Enzyme: Unique Insights from Computational Studies

Trypanosoma cruzi is the causative agent of Chagas disease (CD). So far, 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 plants in the Amaryllidaceae family suppress the growth of Trypanosoma cruzi. 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 validated protein target of Trypanosoma 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 key amino acid residues (Glu230, Tyr342, and Asp59) required for trans-sialidase catalysis. Montanine was the most stable alkaloid throughout the molecular dynamics simulation and had a favorable docking binding energy (-8.9 kcal/mol). Montanine was observed to adopt a unique configuration that enabled it to fit into a hollow cleft of the enzyme, forming strong salt bridge interactions with Asp96. This strong interaction with Asp96 effectively anchored montanine in the active site, creating a closed enzyme conformation that potentially shuts down catalysis. 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, especially montanine, could potentially act as inhibitors of Trypanosoma cruzi trans-sialidase.