Trypanocidal hits identified through Ligand and Structure-based Virtual Screening of Trypanosoma cruzi Trypanothione reductase inhibitors (TcTR)

Chagas is a neglected disease caused by Trypanosoma cruzi and affects > 6 million people worldwide1. Its treatment in Latin America spends R$ 3.77 billion annually2. TcTR is a vital redox enzyme3 where LBVS and SBVS strategies were employed to identify trypanocidal hits. A predictive QSAR model was built for inhibitors obtained from Brenda4 and ChEMBL5 databases. The applicability domain (h* = 0.16) and PCA chemical-biological space were used for LBVS validation with 203 trypanocidal compounds selected from ChEMBL5 database and 10,150 decoys (sensitivity: 0.68, specificity: 0.93 and MCC: 0.68). Additionally, inhibitors and decoys were docked on TcTR (PDB ID: 1BZL6). GOLD7 ChemScore presented best docking (redocking RMSD < 1.5Å) and SBVS validation results (ROC = 0.69 and enrichment factor = 0.40). Pandemic Box10 compounds were evaluated in LBVS and SBVS and the best sixteen compounds were tested single-dose (10uM) in vitro against trypomastigote T. cruzi with four inhibitor compounds.