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- Title
Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen.
- Authors
Olson, Mark A.; Lee, Michael S.; Kissner, Teri L.; Alam, Shahabuddin; Waugh, David S.; Saikh, Kamal U.
- Abstract
In this study, we used high-throughput computational screening to discover drug-like inhibitors of the host MyD88 protein-protein signaling interaction implicated in the potentially lethal immune response associated with Staphylococcal enterotoxins. We built a protein-protein dimeric docking model of the Toll-interleukin receptor (TIR)-domain of MyD88 and identified a binding site for docking small molecules. Computational screening of 5 million drug-like compounds led to testing of 30 small molecules; one of these molecules inhibits the TIR-TIR domain interaction and attenuates pro-inflammatory cytokine production in human primary cell cultures. Compounds chemically similar to this hit from the PubChem database were observed to be more potent with improved drug-like properties. Most of these 2nd generation compounds inhibit Staphylococcal enterotoxin B (SEB)-induced TNF-α, IFN-γ, IL-6, and IL-1β production at 2-10 μM in human primary cells. Biochemical analysis and a cell-based reporter assay revealed that the most promising compound, T6167923, disrupts MyD88 homodimeric formation, which is critical for its signaling function. Furthermore, we observed that administration of a single dose of T6167923 completely protects mice from lethal SEB-induced toxic shock. In summary, our in silico approach has identified anti-inflammatory inhibitors against in vitro and in vivo toxin exposure with promise to treat other MyD88-related pro-inflammatory diseases.
- Subjects
CHEMICAL inhibitors; PROTEIN-protein interactions; CELLULAR signal transduction; IMMUNE response; STAPHYLOCOCCUS toxins; INTERLEUKIN-1 receptors; TUMOR necrosis factors; INTERFERON gamma
- Publication
Scientific Reports, 2015, p14246
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/srep14246