An in silico approach towards the identification of novel inhibitors of the TLR-4 signaling pathway

J Biomol Struct Dyn. 2016 Jun;34(6):1345-62. doi: 10.1080/07391102.2015.1079243. Epub 2015 Sep 2.


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.

Keywords: A46; MM-GBSA; TLR4; TRAM; VIPER; docking; homology modeling; induced-fit docking; innate immunity; molecular dynamics simulations; sepsis; therapeutics; virtual screening.

MeSH terms

  • Binding Sites
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Computer Simulation
  • Drug Discovery*
  • Ligands*
  • Models, Molecular*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / chemistry*
  • Toll-Like Receptor 4 / metabolism


  • Carrier Proteins
  • Ligands
  • Peptides
  • Toll-Like Receptor 4