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3,6‐Dihydroxyflavone: A Potent Inhibitor with Anti‐Inflammatory Activity Targeting Toll‐like Receptor 2
Author(s) -
Balasubramanian Pavithra K.,
Kim Jieun,
Son Kkabi,
Durai Prasannavenkatesh,
Kim Yangmee
Publication year - 2019
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.11644
Subject(s) - tlr2 , hek 293 cells , chemistry , toll like receptor , receptor , pharmacology , innate immune system , microbiology and biotechnology , biochemistry , biology
Toll‐like receptors are membrane‐bound proteins which plays a vital role in the regulation of innate immune response which is involved in various inflammatory disorders. 3,6‐Dihydroxyflavone (3,6‐DHF) is a known chemo preventive agent which is used in the treatment of various cancers including breast cancer and an effective JNK kinase inhibitor which can efficiently block the TLR2‐mediated signaling pathways. In this current study, we have explored inhibition of 3,6‐DHF in TLR2/TLR1 heterodimerization. We stimulated HEK cells by Pam 3 CSK 4 which specifically induced inflammation through TLR2/TLR1 binding. Secretion of the inflammatory cytokine in Pam 3 CSK 4 ‐induced HEK293‐hTLR2 cells was considerably reduced by 3,6‐DHF, implying that 3,6‐DHF inhibited Pam 3 CSK 4 ‐induced TLR2/TLR1 signaling specifically. In addition, 3,6‐DHF did not cause severe cytotoxicity against human embryonic kidney (HEK) cells at high concentration up to 100 μM. The binding affinity of 3,6‐DHF to TLR2 and TLR1 was explored with 10 −5 affinity using bio‐layer interferometry and molecular docking studies identified the important active site residues that participate in the inhibition of TLR2/TLR1 heterodimerization. Our results showed that 3,6‐DHF inhibits TLR2‐mediated inflammatory signaling by direct binding and the insights in designing more potent drug candidates by targeting the interacting crucial active site residues in TLR2/TLR1.