通过计算机筛选合理设计新型 TLR4 配体，并在体外对其功能和结构进行表征。
Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro.
机构信息
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Intensive Medicine and Forensic Science, Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00 Ostrava, Czech Republic.
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
出版信息
Eur J Med Chem. 2018 Feb 25;146:38-46. doi: 10.1016/j.ejmech.2017.12.074. Epub 2018 Jan 11.
The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2.
本研究的目的是鉴定新的小分子，这些小分子具有与髓样分化蛋白 2（hTLR4/MD2）相关的人 toll 样受体 4 的活性。根据当前合理药物设计原则，我们首先对超过 130000 种化合物进行了基于配体和结构的虚拟筛选，以发现迄今为止未知的 hTLR4/MD2 调节剂类，可作为新型免疫佐剂。计算机研究的核心是使用 peta-flops 规模的超级计算机对部分柔性 hTLR4/MD2 受体模型中的柔性配体进行分子对接。从这项研究中得到的最有前途的物质与蒽醌-琥珀酰亚胺杂合体有关，已经合成并进行了测试。制备效果最好的候选物在表达 hTLR4/MD2 的细胞系中表现出 80%的单磷酰脂质 A 的体外激动活性。
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