Evaluation of Dillenia indica L. phytochemicals in identifying promising anti-nephropathic modulators targeting RAGE/NF-κB signalling in diabetic nephropathy: A computational approach

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Introduction Excess formation of AGEs (Advanced Glycation End Products) and increased AGE-RAGE (Receptor for Advanced Glycation End Products) interaction with resultant activation of NF-κB (Nuclear Factor Kappa B) signaling are implicated in the pathogenesis of diabetic nephropathy (DN). Interrupting RAGE-mediated NF-κB signaling could be a therapeutic option to treat DN and other AGEs mediated pathologies. Method In this study, the potential of phytochemicals identified from the methanolic leaf extract of Dillenia indica (DI) to interfere with the AGEs-RAGE axis and NF-κB activation using molecular docking, ADME-Tox and molecular dynamic simulation were investigated in silico approaches. Result Using molecular docking screening of 78 DI phytocompounds identified from GC-MS and LC-MS chromatographic techniques, it was found that some compounds such as Somniferine, Catechin, Butin, Cancentrine, Dipiperamide A and O-Methylsomniferine showed indeed better binding with RAGE and NF-κB while Secoisotetrandrine was comparable to the control drugs. ADME-Tox profiling revealed that Secoisotetrandrine had strong affinity to interact with both RAGE and NF-κB with predicted non-nephrotoxicity. Molecular dynamics simulations further revealed structural binding of Secoisotetrandrine with RAGE and NF-κB protein complexes using RMSD, RMSF & RG analysis throughout the trajectory. MMGBSA free binding energy analysis of the bound complexes demonstrated Secoisotetrandrine with superior stability due to stronger dispersion and hydrophobic contributions, although more stable H-bond interactions were observed in positive controlprotein complexes. Discussion AGEs accumulation and their interaction with RAGE contribute to increased intracellular ROS and activate self-perpetuating NF-κB loop. Virtual screening revealed Secoisotetrandrine with stable binding interaction and structural affinity with RAGE and NF-κB, indicating it could interrupt RAGE-mediated NF-κB interaction and might act as a valuable therapeutic way in providing renoprotection from elevated oxidative stress and inflammation in diabetic influenced renal cells. Conclusion The present study evaluates the antioxidant potential of the plant along with the bioactive metabolites from the methanolic extract, which identifies Secoisotetrandrine from the methanolic extract of Dillenia indica leaves by interrupting RAGE/NF-κB signaling. The study predicts Secoisotetrandrine as a potential candidate with favourable drug-likeness and pharmacokinetic properties and as a promising RAGE/NF-κB inhibitor and renoprotective agent. However, further evaluations are needed for its in vitro and in vivo studies as a therapeutic agent against Diabetic Nephropathy.