Blood Transfusion Centre of Slovenia, Ljubljana, Slovenia.
Eur J Med Chem. 2013;70:393-9. doi: 10.1016/j.ejmech.2013.10.019. Epub 2013 Oct 12.
Toll-like receptor 4 (TLR4) in complex with its accessory protein MD-2 represents an emerging target for the treatment of severe sepsis and neuropathic pain. We performed structure-based and ligand-based virtual screening targeting the TLR4-MD-2 interface. Three in silico hit compounds showed promising TLR4 antagonistic activities with micromolar IC50 values. These compounds also suppressed cytokine secretion by human peripheral blood mononuclear cells. The specific affinity of the most potent hit was confirmed by surface plasmon resonance direct-binding experiments. The results of our study represent a very promising starting point for the development of potent small-molecule antagonists of TLR4.
Toll 样受体 4（TLR4）与其辅助蛋白 MD-2 形成复合物，成为治疗严重败血症和神经病理性疼痛的新兴靶点。我们针对 TLR4-MD-2 界面进行了基于结构和基于配体的虚拟筛选。三种基于计算机的命中化合物显示出有希望的 TLR4 拮抗活性，其 IC50 值为微摩尔级。这些化合物还抑制了人外周血单核细胞的细胞因子分泌。通过表面等离子体共振直接结合实验证实了最有效命中化合物的特异性亲和力。我们的研究结果为开发有效的 TLR4 小分子拮抗剂提供了非常有前途的起点。
