Fragment Pharmacophore-Based Screening: An Efficient Approach for Discovery of New Inhibitors of Toll-Like Receptor 5.
OBJECTIVE
Rheumatoid Arthritis (RA) is a progressing autoimmune inflammatory disease of joint, hallmarked by inflammation, pain and atrophy of bones. Toll-like receptor 5 (TLR5) is a novel inflammatory mediator in RA, and TLR5 inhibitors are speculated to have a therapeutic potential for the treatment of RA.


METHODS
Here we applied fragment pharmacophore-based virtual screening to identify novel TLR5 ligands.


RESULTS
Among compounds collected from Otava peptidomimetic compounds, Maybridge fragment and ZINC libraries, 3355 compounds were selected for docking into the flagellin-binding site of TLR5. 16 compounds with the required interaction, critical amino acid residues and the binding free energies <-7 kcal/mol were identified as potential TLR5 inhibitors, one of which was followed up by molecular dynamics simulation.


CONCLUSIONS
These compounds open a possibility to discover novel TLR5 inhibitors for the treatment of RA.
Hoora
H
Hashemi
Malihe
M
Hassanzadeh
Department of Medicinal Chemistry &amp; Drug Design and Development Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box: 14155-6451, Tehran, Iran.. Iran, Islamic Republic of.
Massoud
M
Amanlou
D055808:Drug Discovery; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D057786:Peptidomimetics; D051198:Toll-Like Receptor 5 / Q000037:antagonists & inhibitors*
D057786:Peptidomimetics; D051198:Toll-Like Receptor 5
Fragment-based; TLR5; molecular docking; molecular dynamics.; pharmacophore model; virtual screening