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

[ Vol. 19 , Issue. 10 ]

Author(s):

Hoora Hashemi, Malihe Hassanzadeh and Massoud Amanlou   Pages 834 - 840 ( 7 )

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.

Affiliation:

Department of Medicinal Chemistry & Drug Design and Development Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box: 14155-6451, Tehran, Iran.



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