Characterization of Growth Differentiation Factors as Inhibitors of TNF-Alpha and IL-6 in Immune-Mediated Inflammatory Disease Rheumatoid Arthritis.

Tumor necrosis factor alpha (TNF-) plays a critical role in the progression of inflammation and affects the cells of the synovial membrane. Another key factor in the progression of rheumatoid inflammation is interleukin-6 (IL-6). Both TNF- and IL-6 promote the proliferation of synovial membrane cells thus stimulating the production of matrix metalloproteinases and other cytotoxins and leading towards bone erosion and destruction of the cartilage. Growth differentiation factor-11 (GDF11) and growth differentiation factor-8 (GDF8) which is also known as myostatin are members of the transforming growth factor- family and could be used as antagonists to inflammatory responses which are associated with rheumatoid arthritis. In the current study, to elucidate the evolutionary relationships of GDF11 with its homologs from other closely related organisms, a comprehensive phylogenetic analysis was performed. From the phylogram, it was revealed that the clade of Primates that belong to superorder Euarchontoglires showed close evolutionary relationships with order Cetartiodactyla of the Laurasiatheria superorder. Fifty tetrapeptides were devised from conserved regions of GDF11 which served as ligands in protein-ligand docking against TNF- and IL-6 followed by drug scanning and ADMET profiling of best selected ligands. The peptides SAGP showed strong interactions with IL-6, and peptides AFDP and AGPC showed strong interactions with TNF-, and all three peptides fulfilled all the pharmacokinetic parameters which are important for bioavailability. The potential of GDF8 as an antagonist to TNF- and IL-6 was also explored using a protein-protein docking approach. The binding patterns of GDF8 with TNF- and IL-6 showed that GDF8 could be used as a potential inhibitor of TNF- and IL-6 to treat rheumatoid arthritis.