Scientists from National and Kapodistrian University of Athens has found two dual inhibitors of proteins involved in chronic inflammatory diseases, by using a newly developed computer-based drug screening platform. These inhibitors may improve treatment of these diseases. The paper “Cheminformatics-aided discovery of small-molecule Protein-Protein Interaction (PPI) dual inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL)” is published in 20 April 2017 in PLoS Computational Biology. Tumor necrosis factor (TNF) is a proinflammatory cytokine that is mainly secreted by macrophages, the key components of the immune system. This cytokine has been implicated in many human diseases, such as ankylosing spondylitis, hidradenitis suppurativa, inflammatory bowel disease, psoriasis, refractory asthma, and rheumatoid arthritis. Therapeutic agents that inhibit TNF's function are considered a potent treatment for these diseases. But some patients are unresponsive to this type of treatment. TNF binds to and thus functions through its receptors. To suppress harmful effects of TNF, efforts have focused on blocking TNF binding to its receptors. However, using molecules that directly disrupt the interaction between TNF and its receptors may have disadvantages, such as poor selectivity and cell toxicity. It is essential to develop novel therapies. The aim of this study is to identify novel TNF inhibitor candidates with reduced toxic effects and high potency. Lead researcher George Kollias and colleagues developed a computer-based drug screening platform. Using the platform, they screened 14,400 small molecules with unknown activity to determine their interactions with TNF. Nine of the 14,400 molecules were identified to disrupt the protein-protein interactions leading to the activation of TNF. Next, the researchers tested the nice molecules with in vitro experiments, and identified two of them, T8 and T23, as the most potent TNF inhibitors. The two molecules bind to TNF as well as RANKL, and prevent their interactions with other proteins. RANKL, or called Receptor activator of nuclear factor kappa-B ligand, is another member of the TNF superfamily and also implicated in chronic inflammatory diseases. Taken together, the data demonstrated that T8 and T23 act as dual inhibitors of TNF and RANKL. These compounds present low toxicity and could be optimized to develop new TNF and RANKL inhibitors for inflammatory diseases. (Cusabio offers TNF and RANKL and Recombinant Adrb2.)