Drug repositioning targeting the Nucleoside Diphosphate Kinase 1 of Trypanosoma cruzi: an in silico approach

GALCERAN F; MARTÍNEZ SAYÉ M; REIGADA C; RENGIFO M; PEREIRA CA; MIRANDA MR

Congreso; XXXII Molecular Parasitology Meeting; 2021

Marine Biological Laboratory, Woods Hole

Nucleoside Diphosphate Kinases (NDPKs) are ubiquitous multifunctional enzymes linked toseveral high profile pathways such as the purine salvage pathway, where NDPKs catalyze theinterconversion between di- and tri-phosphate nucleosides. The mentioned mechanism is arelevant process in Trypanosoma cruzi, carried out by TcNDPK1, since it lacks de novo purinesynthesis. Considering that the TcNDPK1 is the unique canonical NDPK in the parasite, we regardthis enzyme as an interesting and potential target for the usage of computational techniques inpursuit of novel inhibitory drugs to kill the parasite. In the present work we initiated the searchfor NDPK inhibitors by implementing two strategies: ligand based and receptor based virtualscreening. For the first one, we used as our query structural and chemical properties ofexperimental inhibitors obtained from bibliography. Running OpenEye software, we applied thisstrategy on the FDA and SweetLead databases (⋍12,000 worldwide approved drugs). For thesecond approach, we compared TcNDPK1´s sequence with the human ortholog and executed thesearch for potential binding sites, obtaining several differential residues within the active site andthe oligomerization domain. After characterizing these areas we performed molecular dockingof the mentioned databases using two docking software (vina and FRED). By applying thesetechniques and cross-comparing the results we obtained more than 50 commercially availableand 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 andtrypanocidal agents.