An in silico approach towards the identification of novel inhibitors of the TLR-4 signaling pathway. Issue 6 (2nd June 2016)

• Record Type: Journal Article
• Authors: Mahita, Jarjapu; Harini, K.; Rao Pichika, Mallikarjuna; Sowdhamini, Ramanathan
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 34:Issue 6(2016)
• Page Start: 1345
• Page End: 1362
• Publication Date: 2016-06-02
• Subjects: innate immunity -- TLR4 -- TRAM -- A46 -- VIPER -- sepsis -- homology modeling -- docking -- virtual screening -- MM-GBSA -- molecular dynamics simulations -- induced-fit docking -- therapeutics; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2015.1079243
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract : 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.