Targeting drug-resistant cancers: in silico repurposing of the cholesterol-lowering drug Ezetimibe for selective inhibition of aldo-keto reductase 1B10 (AKR1B10).

Abstract

One of the major challenges in cancer treatment is drug resistance, often driven by overexpression of detoxifying enzymes such as aldo-keto reductase family 1 member B10 (AKR1B10). Highly expressed in several cancers, AKR1B10 contributes to chemotherapeutic failure by promoting drug detoxification. Targeting this enzyme could help overcome resistance. In this study, an in silico drug repurposing approach was applied to screen 2,468 FDA-approved drugs from DrugBank for selective AKR1B10 inhibition. A multi-stage molecular docking strategy followed by binding free energy analysis identified ten potential inhibitors with docking scores between ‒10.11 and ‒11.27 kcal/mol and binding energies ranging from ‒31.00 to ‒81.54 kcal/mol. Ezetimibe, a cholesterol-lowering agent, emerged as the top hit with the highest binding energy (‒81.54 kcal/mol) to wild-type AKR1B10. Mutational analysis revealed reduced binding to Lys125, Val301, and Gln303 variants, highlighting residue-specific interactions. Ezetimibe showed weak binding to AKR1B1 (‒17.32 kcal/mol), supporting selectivity. Molecular dynamics simulations (100 ns) confirmed complex stability with average RMSD and RMSF values of 1.29 Å and 0.73 Å, respectively. Quantum mechanical analysis indicated favourable electronic properties and chemical stability. These results suggest that Ezetimibe is a selective and stable AKR1B10 inhibitor, warranting further investigation for drug-resistant cancer therapy.