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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and characterization of new potent TLR7 antagonists based on analysis of the binding mode using biomolecular simulations
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Synthesis and characterization of new potent TLR7 antagonists based on analysis of the binding mode using biomolecular simulations

机译：基于使用生物分子模拟分析结合模式的新高效TLR7拮抗剂的合成与表征

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Aberrant activation of the endosomal Toll-like receptor 7 (TLR7) has been implicated in myriad autoimmune diseases and is an established therapeutic target in such conditions. Development of diverse TLR7 antagonists is mainly accomplished through random screening. To correlate human TLR7 (hTLR7) antagonistic activity with the structural features in different chemotypes, we derived a hypothetical binding model based on molecular docking analysis along with molecular dynamics (MD) simulations study. The binding hypothesis revealed different pockets, grooves and a central cavity where ligand-receptor interaction with specific residues through hydrophobic and hydrogen bond interactions take place, which correlate with TLR7 antagonistic activity thus paving the way for rational design using varied chemotypes. Based on the structural insight thus gained, TLR7 antagonists with quinazoline were designed to understand the effect of engagement of these pockets as well as boundaries of the chemical space associated with them. The newly synthesized most potent hTLR7 antagonist, i.e. compound 63, showed IC50 value of 1.03 +/- 0.05 mu M and was validated by performing primary assay in human plasmacytoid dendritic cells (pDC) (IC50pDC: 1.42 mu M). The biological validation of the synthesized molecules was performed in TLR7-reporter HEK293 cells as well as in human plasmacytoid dendritic cells (pDCs). Our study provides a rational design approach thus facilitating further development of novel small molecule hTLR7 antagonists based on different chemical scaffolds. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：内体Toll样受体7（TLR7）的异常激活与多种自身免疫性疾病有关，是此类疾病的既定治疗靶点。多种TLR7拮抗剂的开发主要通过随机筛选完成。为了将人类TLR7（hTLR7）拮抗活性与不同化学类型的结构特征相关联，我们基于分子对接分析和分子动力学（MD）模拟研究，推导了一个假设的结合模型。结合假说揭示了配体-受体通过疏水和氢键相互作用与特定残基发生相互作用的不同口袋、凹槽和中心腔，它们与TLR7拮抗活性相关，从而为使用不同化学类型进行合理设计铺平了道路。基于由此获得的结构洞察力，设计了含喹唑啉的TLR7拮抗剂，以了解这些口袋的接合效果以及与之相关的化学空间的边界。新合成的最有效的hTLR7拮抗剂，即化合物63，显示IC50值为1.03+/-0.05μM，并通过在人浆细胞样树突状细胞（pDC）中进行初步测定进行验证（IC50pDC:1.42μM）。在TLR7 reporter HEK293细胞以及人浆细胞样树突状细胞（PDC）中对合成的分子进行了生物学验证。我们的研究提供了一种合理的设计方法，从而促进了基于不同化学支架的新型小分子hTLR7拮抗剂的进一步开发。（C） 2020年爱思唯尔马森SAS。版权所有。

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