Novel acridone derivatives as potential P2Y ₁₂ receptor inhibitors: integrating computational modeling and experimental analysis

The combination of clopidogrel and acetylsalicylic acid is the standard treatment for atherosclerotic cardiovascular disease. Nonetheless, there is a pressing need for more potent P2Y12 receptor inhibitors with quicker onset, especially for early intervention in acute myocardial infarction. Integrating computational modeling, i.e. pharmacophore modeling, molecular docking, and dynamics, with empirical data guides the development of effective antiplatelet therapies. This multidisciplinary study employs computational modeling and in-vitro experimental analysis, demonstrating significant inhibition of P2Y12 activity by two NCI compounds namely: NSC380324 and NSC618163. Both NSC380324 and NSC618163 exhibited a platelet reactivity index (%PRI) of 30.0% and 34.0%, respectively compared to cangrelor that demonstrated superior activity, with a %PRI of 11.0% in platelet vasodilator-stimulated phosphoprotein (VASP) assay. Molecular docking simulations show strong binding affinities of both compounds, along with strong binding interactions at the P2Y12 binding site. Importantly, molecular dynamics simulations highlight the influence of receptor dynamics on practical efficacy, suggesting that NSC380324, a promising P2Y12 antagonists indicated by its excellent stability profiles at the binding pocket of P2Y12, its hydrogen-bond interactions occupancies and the average MM-PBSA total binding energy of −38.17 kcal/mol, require further structural optimization and in-vivo studies to realize their full potential for clinical application.