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首页> 外文期刊>Biochemical Pharmacology >Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening
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Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening

机译：通过基于结构的虚拟筛选鉴定作为有效和选择性人TLR2拮抗剂的吡羟镓衍生物

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摘要

Toll-like receptor 2 (TLR2) induces early inflammatory responses to pathogen and damage-associated molecular patterns trough heterodimerization with either TLR1 or TLR6. Since overstimulation of TLR2 signaling is linked to several inflammatory and metabolic diseases, TLR2 antagonists may provide therapeutic benefits for the control of inflammatory conditions. We present virtual screening for the identification of novel TLR2 modulators, which combines analyses of known ligand sets with structure-based approaches. The 13 identified compounds were pharmacologically characterized in HEK293-hTLR2 cells, THP-1 macrophages and peripheral blood mononuclear cells for their ability to inhibit TLR2-mediated responses. Four out of 13 selected compounds show concentration-dependent activity, representing a hit rate of 31%. The most active compound is the pyrogallol derivative MMG-11 that inhibits both TLR2/1 and TLR2/6 signaling and shows a higher potency than the previously discovered CU-CPT22. Concentration ratio analysis identified both compounds as competitive antagonists of Pam(3)CSK(4)- and Pam(2)CSK(4)- induced responses. Schild plot analysis yielded apparent pA(2) values of 5.73 and 6.15 (TLR2/1), and 5.80 and 6.65 (TLR2/6) for CU-CPT22 and MMG-11, respectively. MMG-11 neither shows cellular toxicity nor interference with signaling induced by other TLR agonists, IL-1 beta or TNF. Taken together, we demonstrate that MMG-11 is a potent and selective TLR2 antagonist with low cytotoxicity ren dering it a promising pharmacological tool for the investigation of TLR signaling and a suitable lead structure for further chemical optimization.
机译：Toll样受体2（TLR2）诱导与TLR1或TLR6的病原体和损伤相关的分子模式的早期炎症反应。由于TLR2信号传导的过度刺激与几种炎症和代谢疾病相关联，因此TLR2拮抗剂可以为控制炎性病症提供治疗益处。我们向虚拟筛选用于识别新型TLR2调节器，其将已知配体集的分析与基于结构的方法相结合。将13个鉴定的化合物在HEK293-HTLR2细胞中药学表征，THP-1巨噬细胞和外周血单核细胞，用于抑制TLR2介导的反应的能力。 13种选定化合物中的四种表现出浓度依赖性活性，代表率为31％。最活跃的化合物是染色剂衍生物MMG-11，其抑制TLR2 / 1和TLR2 / 6信号传导，并且显示比先前发现的Cu-CPT22更高的效力。浓缩比分析将化合物鉴定为PAM（3）CSK（4） - 和PAM（2）CSK（4）诱导的反应的竞争性拮抗剂。 SCHILD绘图分析分​​别产生明显的PA（2）值为5.73和6.15（TLR2 / 1）和5.80和6.65（TLR2 / 6），分别用于CU-CPT22和MMG-11。 MMG-11既不显示细胞毒性也不会对其他TLR激动剂，IL-1β或TNF引起的信号传导的干扰。我们携带在一起，我们证明MMG-11是一种具有低细胞毒性REN的有效和选择性的TLR2拮抗剂，其致致其有望的药理学工具，用于研究TLR信号传导和适用于进一步的化学优化的合适的铅结构。

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