A Novel Approach for Apical Periodontitis Prevention Through RIPK۳ Inhibition Using Organic Flavonoids

Background: Apical periodontitis (AP) entails inflammatory bone resorption facilitated by the induction of necroptosis through receptor-interacting protein kinase ۳ (RIPK۳). Consequently, the inhibition of RIPK۳ holds the potential for favorable effects in addressing AP. A comprehensive investigation, encompassing ۴۴ flavonoids, was undertaken to identify potential inhibitors of RIPK۳. Methods: The crystal structure of the RIPK۳ catalytic domain (PDB ID: ۷MON) underwent meticulous preparation through the removal of ligands and energy optimization. Overall, ۴۴ flavonoids were examined in this study. Utilizing AutoDock ۴.۰, molecular docking analyses were performed to evaluate the binding energies within the active site of RIPK۳ 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 RIPK۳. Results: Five distinct flavonoids—orientin, rutin, vicenin-۲, amentoflavone, and nicotiflorin—manifested notable inhibitory effects on RIPK۳, 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 RIPK۳ compared to the reference compound. Conclusion: The proposition arises that flavonoid, particularly orientin, rutin, vicenin-۲, amentoflavone, and nicotiflorin, stand as promising herbal isolates for the therapeutic management of AP.