CONICET | Buscador de Institutos y Recursos Humanos

Enolase is a glycolytic enzyme that catalyzes the interconversion between 2-phosphoglycerate and phosphoenolpyruvate. In trypanosomatids, enolase wasproposed as a key enzyme after in silico and in vivo analysis and it was validated asa protein essential for the survival of the parasite. Therefore, enolase constitutes aninteresting enzyme target for the identification of drugs against Chagas disease. Inthis work, a combined virtual screening strategy was implemented, employingsimilarity virtual screening, molecular docking, and molecular dynamics. First, twoknown enolase inhibitors and the enzyme substrates were used as queries for thesimilarity screening on the Sweetlead database using five different algorithms.Compounds retrieved in the top 10 of at least three search algorithms were selectedfor further analysis, resulting in six compounds of medical use (etidronate,pamidronate, fosfomycin, acetohydroxamate, triclofos, and aminohydroxybutyrate).Molecular docking simulations and pose re-scoring predicted that binding withacetohydroxamate and triclofos would be weak, while fosfomycin andaminohydroxybutyrate predicted binding is experimentally implausible. Dockingposes obtained for etidronate, pamidronate, and PEP were used for moleculardynamics calculations to describe their mode of binding. From the obtained results,we propose etidronate as a potential TcENO inhibitor and describe molecular motifsto be taken into account in the repurposing or design of drugs targeting this enzymeactive site.