Computational identification and evaluation of curcumin derivatives as potential inhibitors of PPP2R5B to enhance insulin sensitivity.

Insulin resistance has been intricately linked to impaired Akt signaling due to the hyperactivation of protein phosphatase 2 A (PP2A). Specifically, the regulatory subunit PPP2R5B plays a crucial role in this dysregulation, making it a promising therapeutic target. This study aimed to identify novel curcumin-derived phytochemicals capable of inhibiting PPP2R5B and improving insulin sensitivity. Initially, approximately 85 curcumin-related compounds were retrieved from the PubChem database and subjected to extensive virtual screening via molecular docking. Among these, curcumin-bicyclopentadione emerged as the lead candidate, exhibiting the strongest binding affinity (− 9.2 kcal mol⁻¹) due to its extensive interactions with key residues ARG64, GLN439, and ARG385. Further MD simulations confirmed their robust binding stability, highlighting sustained hydrogen bonds and minimal structural fluctuations. Pharmacokinetic analyses using DeepPK profiling predicted favorable ADMET properties, including minimal toxicity, no significant cytochrome P450 inhibition, and negligible cardiotoxicity risks. These computational predictions suggest that curcumin-bicyclopentadione and closely related derivatives could effectively inhibit PPP2R5B activity, thereby restoring Akt phosphorylation and insulin-mediated glucose uptake. While promising, these findings necessitate subsequent validation through rigorous experimental assays. The integration of computational and experimental methodologies may ultimately facilitate the development of novel curcumin-based interventions for insulin resistance and associated metabolic disorders, expanding the therapeutic utility of phytochemicals in metabolic disease management.