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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

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

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

Volume 19, Issue 10, 2016

Page: [834 - 840] Pages: 7

DOI: 10.2174/1386207319666160907103507

Price: $65

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.


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