Anti-inflammatory potential of selective small compounds by targeting TNF-α & NF-kB signaling: a comprehensive molecular docking and simulation study

Tumor necrosis factor alpha (TNF-a) is the major cause of inflammation in autoimmune diseases like rheumatoid arthritis (RA). It's mechanisms of signal transduction through nuclear factor kappa B (NFkB) pathway via small molecules such as metabolite crosstalk are still elusive. In this study, we have targeted TNF-alpha and NF-kB through metabolites of RA, to inhibit TNF-alpha activity and deter NF-kB signaling pathways, thereby mitigating the disease severity of RA. TNF-alpha and NF-kB structure was obtained from PDB database and metabolites of RA were selected from literature survey. In-silico studies were carried out by molecular docking using AutoDock Vina software and further, known TNF-alpha and NF-kB inhibitors were compared and revealed metabolite's capacity to targets the respective proteins. Most suitable metabolite was then validated by MD simulation to verify its efficiency against TNF-alpha. Total 56 known differential metabolites of RA were docked with TNF-alpha and NF-kB compared to their corresponding inhibitor compounds. Four metabolites such as Chenodeoxycholic acid, 2-Hydroxyestrone, 2-Hydroxyestradiol (2-OHE2), and 16-Hydroxyestradiol were identified as a common TNF-a inhibitor's having binding energies ranging from -8.3 to -8.6 kcal/mol, followed by docking with NF-kB. Further, 2-OHE2 was selected because of having binding energy -8.5 kcal/mol, found to inhibit inflammation and the effectiveness was validated by root mean square fluctuation, radius of gyration and molecular mechanics with generalized born and surface area solvation against TNF-alpha. Thus 2-OHE2, an estrogen metabolite was identified as the potential inhibitor, attenuated inflammatory activation and can be utilized as a therapeutic target to disseminate severity of RA. [GRAPHICS] .