Abstract
Tumor necrosis factor-α (TNF-α) is a drug target in rheumatoid arthritis and several other auto-immune disorders. TNF-α binds with TNF receptors (TNFR), located on the surface of several immunological cells to exert its effect. Hence, the use of inhibitors that can hinder the complex formation of TNF-α/TNFR can be of medicinal significance. In this study, multiple chem-informatics approaches, including descriptor-based screening, 2D-similarity searching, and pharmacophore modelling were applied to screen new TNF-α inhibitors. Subsequently, multiple-docking protocols were used, and four-fold post-docking results were analyzed by consensus approach. After structure-based virtual screening, seventeen compounds were mutually ranked in top-ranked position by all the docking programs. Those identified hits target TNF-α dimer and effectively block TNF-α/TNFR interface. The predicted pharmacokinetics and physiological properties of the selected hits revealed that, out of seventeen, seven compounds (4, 5, 10, 11, 13–15) possessed excellent ADMET profile. These seven compounds plus three more molecules (7, 8 and 9) were chosen for molecular dynamics simulation studies to probe into ligand-induced structural and dynamic behavior of TNF-α, followed by ligand-TNF-α binding free energy calculation using MM-PBSA. The MM-PBSA calculations revealed that compounds 4, 5, 7 and 9 possess highest affinity for TNF-α; 8, 11, 13–15 exhibited moderate affinities, while compound 10 showed weaker binding affinity with TNF-α. This study provides valuable insights to design more potent and selective inhibitors of TNF-α, that will help to treat inflammatory disorders.
Highlights
This study focused on the in silico designing and development of new drug-like molecules against Tumor necrosis factor-α (TNF-α) to reduce the inflammation and related disorder caused by dysregulation of TNF-α
IC50 values were selected from a literature survey (Supporting Information, Table S1) and their physicochemical properties including molecular weight, topological polar surface area (TPSA), logP, hydrogen bond donor atoms, hydrogen bond acceptor atoms and number of rotatable bonds were calculated (Table S2)
The “drug-like” subset of Zinc Is Not Commercial (ZINC) database was filtered according to the physicochemical descriptors calculated from forty-one known inhibitors of TNF-α
Summary
Tumor necrosis factor-α (TNF-α), known as cachectin or cachexin, is an important cytokine that plays a role in both pathological and physiological inflammatory processes. TNF-α is involved in several acute phase reactions as it regulates immunity. T-lymphocytes, monocytes and macrophages produces TNF-α in response to immunological reactions that provides immunity to the body. Endothelial cells, cardiac myocytes, adipose tissues, fibroblasts and neurons produce TNF. It acts as an endogenously produced pyrogen that helps in the induction of apoptosis, fever inflammation and cachexia that inhibits
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