Abstract
An in silico drug discovery pipeline for the virtual screening of plant-origin natural products (NPs) was developed to explore new direct inhibitors of TNF and its close relative receptor activator of nuclear factor kappa-B ligand (RANKL), both representing attractive therapeutic targets for many chronic inflammatory conditions. Direct TNF inhibition through identification of potent small molecules is a highly desired goal; however, it is often hampered by severe limitations. Our approach yielded a priority list of 15 NPs as potential direct TNF inhibitors that were subsequently tested in vitro against TNF and RANKL. We thus identified two potent direct inhibitors of TNF function with low micromolar IC50 values and minimal toxicity even at high concentrations. Most importantly, one of them (A11) was proved to be a dual inhibitor of both TNF and RANKL. Extended molecular dynamics simulations with the fully automated EnalosMD suite rationalized the mode of action of the compounds at the molecular level. To our knowledge, these compounds constitute the first NP TNF inhibitors, one of which being the first NP small-molecule dual inhibitor of TNF and RANKL, and could serve as lead compounds for the development of novel treatments for inflammatory and autoimmune diseases.
Highlights
Tumor necrosis factor (TNF) is an important human cytokine (Beutler et al, 1985) that is involved in a number of critical biological processes and diseases, including rheumatoid arthritis, Crohn’s disease, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, AIDS, and cancer (Kollias et al, 1999; Apostolaki et al, 2010)
Dual Natural Product TNF/receptor activator of nuclear factor kappa-B ligand (RANKL) Inhibitors anti-TNF approaches, which eventually resulted in clinical trials that were successfully performed for a variety of chronic inflammatory diseases, including rheumatoid arthritis (Elliott et al, 1993), psoriasis, psoriatic arthritis, Crohn’s disease, juvenile idiopathic arthritis, spondyloarthritis, and Behçet’s disease (Sfikakis, 2010)
The formation of the biologically active TNF homotrimer is prevented by direct TNF inhibitors, such as SPD304, through disruption of the TNF dimer binding to the third subunit (He et al, 2005; Davis and Colangelo, 2012)
Summary
Tumor necrosis factor (TNF) is an important human cytokine (Beutler et al, 1985) that is involved in a number of critical biological processes and diseases, including rheumatoid arthritis, Crohn’s disease, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, AIDS, and cancer (Kollias et al, 1999; Apostolaki et al, 2010). Dual Natural Product TNF/RANKL Inhibitors anti-TNF approaches, which eventually resulted in clinical trials that were successfully performed for a variety of chronic inflammatory diseases, including rheumatoid arthritis (Elliott et al, 1993), psoriasis, psoriatic arthritis, Crohn’s disease, juvenile idiopathic arthritis, spondyloarthritis, and Behçet’s disease (Sfikakis, 2010). Three synthetic antibodies that block the activity of TNF have been reported, namely infliximab, adalimumab, and etanercept (Olsen and Stein, 2004). These expensive agents are frequently used as secondary options for patients with a poor response to regular anti-rheumatic drugs (Chaudhari et al, 2016). It has been shown that the use of small molecules in direct TNF inhibition represents an attractive alternative that offers significant benefits, such as oral administration, shorter half-lives with reduced immunosuppression, and easier manufacturing at a lower cost (Sfikakis, 2010; Lo et al, 2017; Melagraki et al, 2018)
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