An in silico approach towards the identification of novel inhibitors of the TLR-4 signaling pathway.
Title | An in silico approach towards the identification of novel inhibitors of the TLR-4 signaling pathway. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Mahita J, Harini K, Pichika MRao, Sowdhamini R |
Journal | J Biomol Struct Dyn |
Volume | 34 |
Issue | 6 |
Pagination | 1345-62 |
Date Published | 2016 Jun |
ISSN | 1538-0254 |
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. |
DOI | 10.1080/07391102.2015.1079243 |
Alternate Journal | J. Biomol. Struct. Dyn. |
PubMed ID | 26264972 |