{"data":{"id":"10.6084/m9.figshare.c.2112449","type":"dois","attributes":{"doi":"10.6084/m9.figshare.c.2112449","prefix":"10.6084","suffix":"m9.figshare.c.2112449","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Jarjapu Mahita","affiliation":[],"nameIdentifiers":[]},{"name":"K. Harini","affiliation":[],"nameIdentifiers":[]},{"name":"Mallikarjuna Rao Pichika","affiliation":[],"nameIdentifiers":[]},{"name":"Sowdhamini, Ramanathan","nameType":"Personal","givenName":"Ramanathan","familyName":"Sowdhamini","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"An \u003ci\u003ein silico\u003c/i\u003e approach towards the identification of novel inhibitors of the TLR-4 signaling pathway"}],"publisher":"Figshare","container":{},"publicationYear":2015,"subjects":[{"subject":"Biophysics"},{"subject":"Biochemistry"},{"subject":"Medicine"},{"subject":"Cell Biology"},{"subject":"Genetics"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Molecular Biology"},{"subject":"Physiology"},{"subject":"Pharmacology"},{"subject":"Biotechnology"},{"subject":"Immunology"},{"subject":"FOS: Clinical medicine","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Cancer"},{"subject":"Mental Health"},{"subject":"Infectious Diseases"},{"subject":"FOS: Health sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"}],"contributors":[],"dates":[{"date":"2015-12-05","dateType":"Created"},{"date":"2016-04-29","dateType":"Updated"},{"date":"2015","dateType":"Issued"}],"language":null,"types":{"ris":"GEN","bibtex":"misc","citeproc":"article","schemaOrg":"Collection","resourceType":"Collection","resourceTypeGeneral":"Collection"},"relatedIdentifiers":[],"relatedItems":[],"sizes":[],"formats":[],"version":null,"rightsList":[{"rights":"CC-BY","rightsUri":"http://creativecommons.org/licenses/by/3.0/us"}],"descriptions":[{"description":"Precise functioning and fine-tuning of Toll-like receptor 4 (TLR4) signaling is a critical requirement for the smooth functioning of the innate immune system, since aberrant TLR4 activation causes excessive production of pro-inflammatory cytokines and interferons. This can result in life threatening conditions such as septic shock and other inflammatory disorders. The TRIF-related adaptor molecule (TRAM) adaptor protein is unique to the TLR4 signaling pathway and abrogation of TRAM-mediated TLR4 signaling is a promising strategy for developing therapeutics aimed at disrupting TRAM interactions with other components of the TLR4 signaling complex. The VIPER motif from the vaccinia virus-producing protein, A46 has been reported to disrupt TRAM-TLR4 interactions. We have exploited this information, in combination with homology modeling and docking approaches, to identify a potential binding site on TRAM lined by the BB loop and αC helix. Virtual screening of commercially available small molecules targeting the binding site enabled to short-list 12 small molecules to abrogate TRAM-mediated TLR4 signaling. Molecular dynamics and molecular mechanics calculations have been performed for the analysis of these receptor-ligand interactions.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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