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首页> 外文期刊>The FEBS journal >Toll-like receptor 2 antagonists identified through virtual screening and experimental validation
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Toll-like receptor 2 antagonists identified through virtual screening and experimental validation

机译：通过虚拟筛选和实验验证确定的Toll样受体2拮抗剂

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摘要

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 nonpeptide TLR2 antagonists, C11 and C13, through pharmacophore-based virtual screening. At 10m, the level of interleukin (IL)-8 inhibition by C13 and C11 in human embryonic kidney TLR2 overexpressing cells was comparable to the commercially available TLR2 inhibitor CU-CPT22. In addition, C11 and C13 acted in mouse macrophage-like RAW 264.7 cells as TLR2-specific inhibitors and did not suppress the tumor necrosis factor- induction by TLR3 and TLR4 activators. Moreover, the two identified compounds bound directly to the human recombinant TLR2 ectodomain, during surface plasmon resonance analysis, and did not affect cell viability in a 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 as TLR2 antagonists, and thus will provide new insights into the structure of TLR2 antagonists, and pave the way for the development of TLR2-targeted drug molecules.
机译：Toll样受体2（TLR2）拮抗剂是关键治疗靶标，因为它们抑制了由剩余TLR2活化引起的几种炎症疾病。在这项研究中，我们通过基于药仔基团的虚拟筛选鉴定了两种新的非肽TLR2拮抗剂，C11和C13。在10M时，人胚胎肾TLR2过表达细胞C13和C11的白细胞介素（IL）-8抑制水平与市售的TLR2抑制剂Cu-CPT22相当。此外，C11和C13在小鼠巨噬细胞样原料264.7细胞中作为TLR2特异性抑制剂作用，并且没有抑制TLR3和TLR4活化剂的肿瘤坏死因子。此外，在表面等离子体共振分析期间，将两种鉴定的化合物直接结合到人重组TLR2胞外域，并且在3-（4,5-二甲基噻唑-2-基）-5（3-羧甲苯酚）中不影响细胞活力 - 2-（4-硫苯基）-2H-四唑鎓测定。总共有两种几乎筛选的分子，C11和C13，被实验证明是有效的TLR2拮抗剂，因此将对TLR2拮抗剂的结构提供新的见解，并为发展TLR2靶向药物分子铺平道路。

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