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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 2 nd  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.

Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen