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10.1038/srep14246 http://scihub22266oqcxt.onion/10.1038/srep14246 C4585646!4585646 !26381092     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26381092 &cmd=llinks): Failed to open stream: HTTP request failed! 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Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen |pdf=|usr=}}{{26381092 }} gab.com Text Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen JO: Sci Rep http://www.kidney.de/pget.php?&tw=1&pmid=26381092 #FOAvip 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-?, IFN-?, IL-6, and IL-1? production at 2-10 ?M 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. Twit Text FOAVip Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen ????Sci Rep http://www.kidney.de/pget.php?&tw=1&pmid=26381092 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26381092 #FOAvip English Wikipedia <ref>{{Cite pmid|26381092 }}</ref> Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen #MMPMID26381092 Olson MA ; Lee MS ; Kissner TL ; Alam S ; Waugh DS ; Saikh KU Sci Rep 2015[Sep]; 5 (ä): 14246 PMID26381092 show ga 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-?, IFN-?, IL-6, and IL-1? production at 2-10 ?M 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. |*Computer Simulation [MESH] |*Signal Transduction/drug effects [MESH] |Animals [MESH] |Computational Biology/*methods [MESH] |Cytokines/metabolism [MESH] |Dose-Response Relationship, Drug [MESH] |Drug Discovery/*methods [MESH] |Enterotoxins/immunology/metabolism [MESH] |Humans [MESH] |Inflammation Mediators/metabolism [MESH] |Inhibitory Concentration 50 [MESH] |Leukocytes, Mononuclear/drug effects/immunology/metabolism [MESH] |Mice [MESH] |Models, Molecular [MESH] |Myeloid Differentiation Factor 88/*chemistry/*metabolism [MESH] |Protein Binding [MESH] |Protein Conformation [MESH] |Protein Interaction Domains and Motifs [MESH]Discovery of small molecule inhibitors of MyD88-dependent signaling pa(epmc).pdf DeepDyve Pubget Overpricing