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

Abstract

Tumor necrosis factor alpha (TNF-α) 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-α 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-β 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-α 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-α, and all three peptides fulfilled all the pharmacokinetic parameters which are important for bioavailability. The potential of GDF8 as an antagonist to TNF-α and IL-6 was also explored using a protein-protein docking approach. The binding patterns of GDF8 with TNF-α and IL-6 showed that GDF8 could be used as a potential inhibitor of TNF-α and IL-6 to treat rheumatoid arthritis.

Figure 1

Phylogenetic relationships of the GDF11 gene in selected organisms. The tree is labeled on the basis of orders and suborders of selected animals. The animals of the same suborder cladded together.

Figure 2

Interactions (a) and binding patterns (b) of TETV with TNF-α.

Figure 3

Interactions (a) and binding patterns (b) of AQET with IL-6.

Figure 4

Protein-protein interactions between myostatin and TNF-α. (a) GDF8/TNF-α docked complex in cartoon representation is shown at the top. Myostatin is shown in green while TNF-α is shown in blue. Interacting residues of the GDF8/TNF-α complex are shown in red color stick representation. (b) All interacting residues of GDF8 and TNF-α. Blue color: H-bonds, red color: salt bridges, yellow color: disulfide bonds, orange color: other contacts. Hydrogen bonds are shown with blue lines. The colors of interacting residues are representing properties of amino acids (i.e., blue: positive, red: negative, green: aliphatic, grey: aliphatic, pink: aromatic, orange: Pro/Gly, and yellow: Cyc).

Figure 5

Protein-protein interactions between myostatin and IL-6. (a) GDF8/IL-6 docked complex in cartoon representation is shown at the top. Myostatin is shown in green, and IL-6 is shown in yellow. Interacting residues of the GDF8/IL-6 complex are shown in red color stick representation. (b) All interacting residues of GDF8 and IL-6. Blue color: H-bonds, red color: salt bridges, yellow color: disulfide bonds, and orange color: nonbonded contacts. Hydrogen bonds are shown with blue lines. The colors of interacting residues are representing properties of amino acids (i.e., blue: positive, red: negative, green: aliphatic, grey: aliphatic, pink: aromatic, orange: Pro/Gly, and yellow: Cyc).