Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic.
Department of Forensic Medicine and Intensive Medicine, Faculty of Medicine, University of Ostrava, Syllabova 19, Ostrava 70300, Czech Republic.
Molecules. 2018 Jan 4;23(1):102. doi: 10.3390/molecules23010102.
In order to identify novel lead structures for human toll-like receptor 4 (TLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the TLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate TLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6.
为了鉴定人 toll 样受体 4（TLR4）调节的新型先导结构，我们使用了 petaflops 级别的超级计算机进行了虚拟高通量筛选。基于计算机模拟研究，我们合理设计了一系列 12 种与色胺有关的化合物，以保持与 TLR4 结合位点相互作用的合适分子几何形状，并满足药物相似性的一般原则。所提出的化合物被合成，并通过体外和体内实验进行了测试，结果表明其中一些化合物在体外能够刺激 TLR4，其活性高达单磷酰脂质 A 的 25%。通过表面等离子体共振直接结合实验证实了体外最有效物质的特定亲和力。此外，该系列中的两种化合物还显示出诱导白细胞介素 6 产生的显著能力。
