info:eu-repo/semantics/article
In silico repositioning of etidronate as a potential inhibitor of the Trypanosoma cruzi enolase
Fecha
2019-12Registro en:
Valera Vera, Edward Augusto; Martínez Sayé, Melisa Soledad; Reigada, Chantal; Miranda, Mariana Reneé; Pereira, Claudio Alejandro; In silico repositioning of etidronate as a potential inhibitor of the Trypanosoma cruzi enolase; Elsevier Science Inc; Journal Of Molecular Graphics & Modelling; 12-2019
1093-3263
CONICET Digital
CONICET
Autor
Valera Vera, Edward Augusto
Martínez Sayé, Melisa Soledad
Reigada, Chantal
Miranda, Mariana Reneé
Pereira, Claudio Alejandro
Resumen
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 as a protein essential for the survival of the parasite. Therefore, enolase constitutes an interesting enzyme target for the identification of drugs against Chagas disease. In this work, a combined virtual screening strategy was implemented, employing similarity virtual screening, molecular docking, and molecular dynamics. First, two known enolase inhibitors and the enzyme substrates were used as queries for the similarity screening on the Sweetlead database using five different algorithms. Compounds retrieved in the top 10 of at least three search algorithms were selected for 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 with acetohydroxamate and triclofos would be weak, while fosfomycin and aminohydroxybutyrate predicted binding is experimentally implausible. Docking poses obtained for etidronate, pamidronate, and PEP were used for molecular dynamics calculations to describe their mode of binding. From the obtained results, we propose etidronate as a potential TcENO inhibitor and describe molecular motifs to be taken into account in the repurposing or design of drugs targeting this enzyme active site.