Determination of the Anti‐Atherosclerotic Potential of Etodolac and Acemetacin Using a Drug Repurposing Approach: Enzyme Inhibition, Cytotoxicity, In Silico Studies

ABSTRACT Atherosclerosis is a chronic vascular disease caused by oxidative stress and inflammation. Cardiovascular regulatory enzymes, such as paraoxonase‐1 (PON1) and angiotensin‐converting enzyme (ACE), are the primary targets for treatment. In this study, the antiatherosclerotic effects of etodolac and acemetacin compounds were evaluated in a multifaceted manner. Within the scope of the study, the interactions of both compounds with the PON1 and ACE target proteins were analyzed via molecular docking, and then the stability of the complexes was evaluated using molecular dynamics (MD) simulations. The pharmacokinetic properties of the compounds were determined using ADME prediction, and the HOMO‐LUMO energies and reactivity parameters were calculated using density functional theory (DFT). Additionally, MTT cytotoxicity assay was performed on a human vascular endothelial cell line (HUVEC) to assess the safety profiles of the compounds at the cellular level. The results revealed that etodolac had significant concentration‐dependent toxicity in HUVECs, whereas acemetacin had a lower cytotoxic effect. According to the molecular modeling results, both compounds showed high binding affinities for the PON1 and ACE enzymes. MD simulations revealed that the complexes remained stable over time. ADME and DFT analyses supported the evaluation of these compounds as potential pharmaceutical candidates. Acemetacin may be considered a safer antiatherosclerotic candidate than the compound etodolac.