Targeting tryparedoxin-dependent peroxidase (TXNPx) enzyme to identify repurposing drug candidates from FDA-approved drugs and natural products using virtual screening, ADME/Tox and MD simulations

Protozoan are parasitic organisms that can cause significant diseases worldwide, such as Chagas disease, African sleeping sickness, and Leishmaniasis. In this study, we performed docking studies on type II tryparedoxin-dependent peroxidase (PDB ID: 2VUP) using a Zinc database having natural products library and FDA-approved drugs. The top compounds identified are F1762–0560, F1855-0030, FDA_339, FDA_461, tetrahydrobenzo-tetraphenoxirene, and ketoconazole. These compounds were further performed the molecular dynamics simulations studies. The docking results has suggested that top Docking Scores compounds are F17620560 (−8.6 kcal/mol), F1855-0030(−7.8 kcal/mol), FDA_339 (−7.0 kcal/mol), FDA_461 (−7.0 kcal/mol), tetrahydrobenzo-tetraphenoxirene (−7.5 kcal/mol) and, ketoconazole (−6.7 kcal/mol). The common binding affinity amino acids are SER 37, LYS 38, CYS 39, LYS 43, GLU 81 and PHE 85. The top scoring compounds (F1762-0560) has showed interactions with the target protein through hydrogen bonding and stacking interactions, particularly with SER 37, CYS 39, and LYS 43. We further investigated the stability of six ligand-TXNPx complexes over 200 ns. The results indicated good structural stability (RMSD: 0.05–0.20 nm; Rg: 1.45–1.52 nm), with F0556–0242 and F1762-0560 showing the least fluctuations. FDA_461 has the most hydrogen bonds (up to 5), while Ketoconazole was more flexible (RMSD peak: 0.25 nm). These findings suggest that F0556–0242, F1762-0560, and FDA_461 are promising candidates.