Biomedicine & Pharmacotherapy (Jan 2022)
The inhibitory role of benzo-dioxole-piperamide on the phosphorylation process as an NF-Kappa B silencer
Abstract
NF-κB contributes to the biosynthesis of various chemokines, cytokines, and enzymes. It plays many crucial roles in the upstream neuroinflammatory pathways. Briefly, the inhibitory IkB subunit is cleaved and phosphorylated by the IKK-α/β enzyme. It leads to the activation and translocation of the NF-κB (p50/p65) complex into the nucleus. Subsequently, the activated NF-κB interacts with the genomic DNA and contributes to expressing various proinflammatory cytokines. In the present study, we developed a novel NF-κB inhibitor encoded (D5) and investigated the efficacy of our druggable compound through several in silico, in vitro, and in situ analysis. The results demonstrated that D5 not only inhibited the mRNA expression of the IKK-α/β enzyme (around 86–96% suppression rate for both cell lines at 12 and 24 h time frames) but also by interacting to the active site of the mentioned kinase (dock score −6.14 and binding energy −23.60 kcal/mol) reduced the level of phosphorylated IkB-α in the cytosol around 96–99% and p65 subunit in the nucleus around 73–90% (among all groups in 12 and 24 h time points). Additionally, the results indicated that D5 suppressed the NF-κB target mRNA levels of TNF-α and IL-6 in a total average of around 92%. Overall, The results demonstrated that D5 in a considerably lower concentration than Dis (0.71 µM vs. 52.73 µM) showed significantly higher inhibitory efficacy on NF-κB translocation approx. 200–300%. The results suggested D5 as a potent NF-κB silencer, but further investigations are required to validate our outcomes.
