Toll-like receptor 2 antagonists identified through virtual screening and experimental validation

TitleToll-like receptor 2 antagonists identified through virtual screening and experimental validation
Publication TypeJournal Article
Year of Publication2017
AuthorsDurai P, Shin HJ, Achek A, Kwon HK, Govindaraj RG, Panneerselvam S, Yesudhas D, Choi J, No KT, Choi S
JournalFEBS J
Date Published2017 Jun 01
ISSN1742-4658
Abstract

Toll-like receptor 2 (TLR2) antagonists are key therapeutic targets because they inhibit several inflammatory diseases caused by surplus TLR2 activation. In this study, we identified two novel non-peptide TLR2 antagonists, C11 and C13, through pharmacophore-based virtual screening. At 10 μM, the level of interleukin-8 inhibition by C13 and C11 in human embryonic kidney TLR2 overexpressing cells is comparable to the commercially available TLR2 inhibitor CU-CPT22. In addition, C11 and C13 act in mouse macrophage-like RAW 264.7 cells as TLR2-specific inhibitors, and do not suppress the tumor necrosis factor-α induced by TLR3 and TLR4 activators. Moreover, the two identified compounds bind directly to the human recombinant TLR2 ectodomain, during surface plasmon resonance analysis, and do not affect cell viability in 3-(4, 5-dimethylthiazol-2-yl)-5 (3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay. In total, two virtually screened molecules, C11 and C13, were experimentally proven to be effective, and thus, will provide new insights into the structure of TLR2 antagonists, and pave the way for the development of TLR2-targeted drug molecules. This article is protected by copyright. All rights reserved.

DOI10.1111/febs.14124
Alternate JournalThe FEBS Journal

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