A Novel Approach for Apical Periodontitis Prevention Through RIPK3 Inhibition Using Organic Flavonoids

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Background: Apical periodontitis (AP) entails inflammatory bone resorption facilitated by the induction of necroptosis through receptor-interacting protein kinase 3 (RIPK3). Consequently, the inhibition of RIPK3 holds the potential for favorable effects in addressing AP. A comprehensive investigation, encompassing 44 flavonoids, was undertaken to identify potential inhibitors of RIPK3. Methods: The crystal structure of the RIPK3 catalytic domain (PDB ID: 7MON) underwent meticulous preparation through the removal of ligands and energy optimization. Overall, 44 flavonoids were examined in this study. Utilizing AutoDock 4.0, molecular docking analyses were performed to evaluate the binding energies within the active site of RIPK3 concerning the examined herbal isolates, with subsequent comparison to the results obtained from a positive control inhibitor. Furthermore, the BIOVIA Discovery Studio Visualizer played a crucial role in elucidating the interactions between the top-ranked flavonoids and the residues of RIPK3. Results: Five distinct flavonoids—orientin, rutin, vicenin-2, amentoflavone, and nicotiflorin—manifested notable inhibitory effects on RIPK3, boasting inhibition constant values at either the femtomolar or picomolar scale. Notably, the first three members of this set showcased superior binding affinity to the active site of RIPK3 compared to the reference compound. Conclusion: The proposition arises that flavonoid, particularly orientin, rutin, vicenin-2, amentoflavone, and nicotiflorin, stand as promising herbal isolates for the therapeutic management of AP.