3,6‐Dihydroxyflavone: A Potent Inhibitor with Anti‐Inflammatory Activity Targeting Toll‐like Receptor 2

• Published in: Bulletin of the Korean Chemical Society Vol. 40; no. 1; pp. 51 - 55
• Main Authors: Balasubramanian, Pavithra K., Kim, Jieun, Son, Kkabi, Durai, Prasannavenkatesh, Kim, Yangmee
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley‐VCH Verlag GmbH & Co. KGaA 01.01.2019; 대한화학회
• Subjects: 3,6‐dihydroxyflavone; Antagonist; Inflammation; TLR1; TLR2; 화학
• ISSN: 1229-5949; 0253-2964; 1229-5949
• DOI: 10.1002/bkcs.11644

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 Pam3CSK4 which specifically induced inflammation through TLR2/TLR1 binding. Secretion of the inflammatory cytokine in Pam3CSK4‐induced HEK293‐hTLR2 cells was considerably reduced by 3,6‐DHF, implying that 3,6‐DHF inhibited Pam3CSK4‐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.