An in silico approach towards the identification of novel inhibitors of the TLR-4 signaling pathway.
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.
a National Centre for Biological Sciences , GKVK Campus, Bangalore , India.
Jarjapu
J
Mahita
a National Centre for Biological Sciences , GKVK Campus, Bangalore , India.
K
K
Harini
b School of Pharmacy , International Medical University , Bukit Jalil, Kuala Lumpur , Malaysia.
Mallikarjuna
M
Rao Pichika
a National Centre for Biological Sciences , GKVK Campus, Bangalore , India.
Ramanathan
R
Sowdhamini
D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D055808:Drug Discovery; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D002352:Carrier Proteins; D008024:Ligands; D010455:Peptides; D051197:Toll-Like Receptor 4
A46; MM-GBSA; TLR4; TRAM; VIPER; docking; homology modeling; induced-fit docking; innate immunity; molecular dynamics simulations; sepsis; therapeutics; virtual screening