In silico drug repurposing to identify activators targeting SLC7A11/xCT for cardiotoxicity: Molecular docking, dynamics simulation, and ADMET analysis

Drug-induced cardiotoxicity remains a major challenge in pharmaceutical development, necessitating the identification of protective agents against cardiac damage. The cystine/glutamate antiporter solute carrier family 7 member 11/ cystine-glutamate antiporter (SLC7A11/xCT) plays a crucial role in cellular defense against oxidative stress by facilitating glutathione synthesis. This study utilized in silico drug repurposing to identify potential xCT activators from a library of approved antibiotics. Molecular docking was employed to assess the binding affinity of 355 drugs, with the control compound MC-100093 demonstrating a binding affinity of −6.7 kcal/mol. Thirty-one drugs exhibited stronger binding, with Daunorubicin showing the highest affinity (−10.8 kcal/mol); however, its known cardiotoxicity excluded it from further analysis. Following absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening, seven drugs were selected based on their adherence to Lipinski’s Rule of Five and favorable pharmacokinetic properties. Notably, dexamethasone and prulifloxacin stood out for their favorable binding affinity and stability in molecular dynamics simulations. Compared to the control, dexamethasone exhibited superior binding affinity (−9.2 kcal/mol) and the most favorable total binding free energy (−14.89 kcal/mol), indicating enhanced stability within the xCT complex. This was further supported by its stable interaction profile, reduced structural fluctuations, and favorable drug-likeness properties. These results suggest that dexamethasone promising candidates for repurposing as cardioprotective agents, offering potential therapeutic options for mitigating drug-induced cardiotoxicity. Further experimental validation is needed to confirm their efficacy in-vivo . GRAPHICAL ABSTRACT Selecting compounds with the possibility of cardioprotective activity.