Fragment Pharmacophore-Based Screening: An Efficient Approach for Discovery of New Inhibitors of Toll-Like Receptor 5

Author(s): Hoora Hashemi, Malihe Hassanzadeh, Massoud Amanlou.

Journal Name:Combinatorial Chemistry & High Throughput Screening

Volume 19 , Issue 10 , 2016

Abstract:

Aim and 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.

Material and method: 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.

Conclusion: These compounds open a possibility to discover novel TLR5 inhibitors for the treatment of RA.

Keywords: Fragment-based, molecular docking, pharmacophore model, TLR5, virtual screening, molecular dynamics.

Rights & PermissionsPrintExport

Article Details

VOLUME: 19
ISSUE: 10
Year: 2016
Page: [834 - 840]
Pages: 7
DOI: 10.2174/1386207319666160907103507
Price: $58