Synergistic targeting of NF-κB by cinnamic and p-coumaric acids: computational and DPPH radical scavenging assessment

Nuclear factor-kappa B (NF-κB) is a key transcription factor implicated in inflammation, immune regulation, and cancer progression, making it an important target for antioxidant and anti-inflammatory therapy for acne. The present study evaluated the synergistic NF-κB inhibitory potential of cinnamic acid and p-coumaric acid (p-CA) through molecular docking analysis, followed by formulation development and antioxidant assessment. Molecular docking was performed using AutoDock Vina v1.2.6 to investigate binding affinity and interaction profiles. Individual formulations containing cinnamic acid (1%) and p-CA (1%), as well as an equimolar combined formulation (0.5% each), were developed using hydrogel and oleogel phases to obtain a bigel system. Antioxidant activity was determined using the DPPH radical scavenging assay. Docking studies demonstrated binding energies of - 4.046 kcal/mol and - 4.400 kcal/mol for cinnamic acid and p-CA, respectively, whereas the combined ligand complex exhibited an enhanced binding affinity of - 7.837 kcal/mol. The improved interaction was stabilized through hydrogen bonding and hydrophobic interactions involving key amino acid residues, including ARG54, LEU251, GLU341, and THR342. In the antioxidant assay at 250 μg/mL, p-CA and cinnamic acid exhibited 16.76% and 14.02% inhibition, respectively, IC50 value of the cinnamic acid, p-coumaric acid and combined was found to be 750 µg/mL, 1160 µg/ mL, 810 µg/mL, while the equimolar bigel formulation demonstrated significantly higher radical scavenging activity (19.95%-28.55%), suggesting a synergistic effect. This research indicates that the combination of cinnamic acid and p-CA enhances molecular interactions with the NF-κB p50 subunit and improves antioxidant activity compared with the individual compounds. These integrated in silico and experimental results support the potential application of this combination in the development of multi-targeted natural formulations.