Molecular Docking, QSAR and Microscopic Studies of Anti-trypanosomal Compounds from the Pathogen Box

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 were described. 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 anti-trypanosomal compounds.