Abstract

Myocardial ischaemia reperfusion (I/R) injury remains a critical challenge in cardiovascular therapy, particularly in patients receiving anthracycline chemotherapy. Doxorubicin, though highly effective as an anticancer agent, is limited by its cardiotoxic effects that are exacerbated during I/R events. Nuclear factor-kappa B (NF-KB), a key transcription factor regulating inflammation and apoptosis, is strongly implicated in this dual-insult mechanism. In this in-silico study, molecular docking and structural analyses were performed to evaluate the interaction between doxorubicin and NF-KB, and to assess the resulting conformational and physicochemical changes. Docking simulations revealed nine binding modes, with Mode-1 showing the strongest affinity (-8.5 kcal/ mol), stabilized by hydrogen bonds, van der Waals forces, and hydrophobic interactions. Hydrophobicity and isotropic displacement analyses demonstrated that doxorubicin binding introduced marked fluctuations and enhanced protein flexibility, leading to structural destabilization. Ramachandran plot evaluation further confirmed significant loss of residues in favorable conformational regions, suggesting impaired folding. Visualization of NF-KB under drug exposure revealed increased intensity and altered spatial distribution, indicative of enhanced activation. Collectively, these findings suggest that doxorubicin modulates NF-KB through strong binding and structural perturbation, thereby amplifying myocardial injury mechanisms. The study provides molecular insights into cardiotoxicity and identifies NF-KB as a potential target for cardioprotective interventions.

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Data Sharing Statement

Funding