Allopurinol as cardioprotective agent in chronic coronary syndrome: In silico evaluation of its potential as Keap1/Nrf2 modulator

Abstract

Chronic coronary syndrome (CCS), a leading cause of global morbidity and mortality, is closely linked to oxidative stress and hyperuricemia. Despite mixed clinical outcomes, allopurinol, a xanthine oxidase inhibitor, has shown potential cardiovascular benefits beyond urate reduction. This study investigates allopurinol’s molecular interactions with the Keap1/Nrf2 pathway, a key regulator of antioxidant responses, using computational approaches. Molecular docking (Glide XP, Schrödinger Maestro) and dynamics simulations (Desmond, OPLS4 force field) analyzed allopurinol’s binding to the Keap1 kelch domain, comparing it to a co-crystallized ligand and inhibitor KI696. Docking revealed moderate affinity for allopurinol (−5.372 kcal/mol), driven by hydrogen bonds (ARG415, SER555) and hydrophobic interactions. Molecular dynamics simulations (100 ns) demonstrated stable binding, with an average RMSD of 3.3 Å. Persistent interactions, including hydrogen bonds with ARG415 and SER555, highlighted allopurinol’s dynamic stability. These findings propose allopurinol as a Keap1 inhibitor, potentially mitigating oxidative stress in CCS. Further experimental is recommended to validate allopurinol’s role in CCS management and bridging computational evidence with clinical application.