Background: Trypanosoma brucei (T. brucei) is the cause of the deadly human African
trypanosomiasis (HAT) with a case fatality ratio of 10%.
Objective: Targeting the essential Trypanosomal glucose metabolism pathway through the inhibition
of phosphoglycerate kinase (PGK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
is a valid strategy for anti-T. brucei drug development.
Methods: Here, quantitative structure activity relationship, molecular docking and microscopic
studies were used to describe the mode of inhibition of selected compounds from the pathogen box
PGK and GAPDH.
Results: We identified 4 hit compounds from the pathogen box with optimal binding and
chemical interactions. Notably, it was identified that interacting charge surface and atomic mass
were key aspects of both PGK and GAPDH inhibition. Also, novel anti-trypanosomal compounds
were identified from the pathogen box and their half maximal inhibitory concentrations
Conclusion: Our study presents new anti-trypanosomal compounds with optimal pharmacological
profiles and an optimization strategy for improving target specificity in the rational design of novel