Computational analysis identifies quinone oxidoreductase as a mitochondrial redox hub associated with drug resistance in Leishmania donovani

Quinone oxidoreductase (QOR) is an enzyme with a critical role in cellular redox homeostasis by protecting against oxidative stress. In the present study, we employed a computational approach to find out the structural features, evolutionary conservation, functional interaction network, ligand binding interaction of parasite QOR. The crystal structure of QOR was validated by confirming the stable architecture and favourable stereochemical conformations for subsequent computational analyses. Relative sequence alignment and phylogenetic analysis of QOR from fourteen Leishmania species demonstrated strong evolutionary conservation, indicating an essential functional role across the genus. Binding pocket prediction showed several surface-accessible cavities, with a dominant central pocket displaying structural features for ligand accommodation. Docking analysis with the clinically utilized antileishmanial drugs showed that amphotericin B, miltefosine, pentamidine, and paromomycin interacted with the residues Phe44, Tyr48, Cys127, Arg268, and Lys181. Pharmacokinetic analysis of drug-ligand interaction showed that miltefosine exhibited the most favorable ADMET profile, while other drugs displayed poor metabolic interactions. Protein–protein interaction network (PPI) analysis further placed QOR within a redox-linked metabolic module which is strongly associated with mitochondrial pathways. Transcriptomic analysis also revealed altered expression of QOR under drug-resistant conditions. Together, these findings highlight the importance of QOR in parasite redox metabolism and as a critical drug target for antileishmanial drug discovery.