title: Structure-based discovery of an immunomodulatory inhibitor of TLR1-TLR2 heterodimerization from a natural product-like database.
abstract: We report herein the identification of an immunomodulatory natural product-like compound as a direct inhibitor of TLR1-TLR2 heterodimerization. Compound suppressed TNF-α and IL-6 secretion in Pam3CSK4-induced macrophages. Moreover, compound inhibited the phagocytic activity of macrophages, presumably through modulation of TLR1-TLR2 signaling and inactivation of NF-κB. Molecular docking revealed that compound bound to the interface region of TLR1-TLR2 by forming two hydrogen bonds with residues lining the binding site. To our knowledge, compound has been only the second inhibitor overall of TLR1-TLR2 heterodimerization reported to date.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. YTWang@umac.mo duncanleung@umac.mo.
authors.forename: Zhangfeng
authors.initials: Z
authors.lastname: Zhong
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Liu
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Dong
authors.forename: Lihua
authors.initials: L
authors.lastname: Lu
authors.forename: Modi
authors.initials: M
authors.lastname: Wang
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D062126:Databases, Chemical; D019281:Dimerization; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D051194:Toll-Like Receptor 1 / Q000037:antagonists & inhibitors*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors*
chemical_list: D001688:Biological Products; D007155:Immunologic Factors; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2