Drug repositioning targeting the Nucleoside Diphosphate Kinase 1 of Trypanosoma cruzi

GALCERAN, FACUNDO; SAYE, MELISA; REIGADA, CHANTAL; RENGIFO, MARCOS; PEREIRA, CA; MIRANDA, MARIANA

Woods hole

Congreso; Molecular Parasitology Meeting XXII; 2021

Marine biological laboratory

Nucleoside Diphosphate Kinases (NDPKs) are ubiquitous multifunctional enzymes linked to several high profile pathways such as the purine salvage pathway, where NDPKs catalyze the interconversion between di- and tri-phosphate nucleosides. The mentioned mechanism is a relevant process in Trypanosoma cruzi, carried out by TcNDPK1, since it lacks de novo purine synthesis. Considering that the TcNDPK1 is the unique canonical NDPK in the parasite, we regard this enzyme as an interesting and potential target for the usage of computational techniques in pursuit of novel inhibitory drugs to kill the parasite. In the present work we initiated the search for NDPK inhibitors by implementing two strategies: ligand based and receptor based virtual screening. For the first one, we used as our query structural and chemical properties of experimental inhibitors obtained from bibliography. Running OpenEye software, we applied this strategy on the FDA and SweetLead databases (⋍12,000 worldwide approved drugs). For the second approach, we compared TcNDPK1´s sequence with the human ortholog and executed the search for potential binding sites, obtaining several differential residues within the active site and the oligomerization domain. After characterizing these areas we performed molecular docking of the mentioned databases using two docking software (vina and FRED). By applying these techniques and cross-comparing the results we obtained more than 50 commercially available and promising compounds, some of them shared outcomes of different procedures (Nebivolol, Micardis, Avodart, etc). The next step will be the evaluation of them as TcNDPK1 inhibitors and trypanocidal agents.