Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of a small-molecule ligand in complex with Toll-like receptor 8 (TLR8) as a model system due to TLR8's clinical relevance. Overactivation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases; however, there are still few small-molecule antagonists available, and our rational designs led to the discovery of six exceptionally potent compounds with ∼picomolar IC50values. Two X-ray crystallographic structures validated the contacts within the binding pocket. A variety of biological evaluations in cultured cell lines, human peripheral blood mononuclear cells, and splenocytes from human TLR8-transgenic mice further demonstrated these TLR8 inhibitors' high efficacy, suggesting strong therapeutic potential against autoimmune disorders.

中文翻译：

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通过基于结构的合理设计的小分子TLR8拮抗剂

基于蛋白质的结构信息来合理设计类似药物的小分子配体仍然是化学生物学中的重大挑战。特别是，鉴于蛋白质表面的动态特性，针对蛋白质-蛋白质界面的设计几乎没有成功。在本文中，由于TLR8的临床意义，我们将与Toll样受体8（TLR8）结合的小分子配体的结构用作模型系统。已经表明，TLR8的过度激活在各种自身免疫性疾病的发病机理中起着重要的作用。但是，仍然没有可用的小分子拮抗剂，而我们的合理设计导致发现了6种具有〜皮摩尔IC50值的异常有效的化合物。两个X射线晶体学结构验证了装订袋内的接触。