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.

这项研究的目的是确定对与髓样分化蛋白2（h TLR4 / MD2）相关的人类通行费样受体4具有活性的新小分子。遵循当前合理的药物设计原则，我们首先对超过13万种化合物进行了基于配体和结构的虚拟筛选，以发现迄今未知的可用作新型免疫佐剂的h TLR4 / MD2调节剂。计算机模拟研究的核心是将柔性配体分子对接在部分柔性h中使用peta-flops级超级计算机的TLR4 / MD2受体模型。合成并测试了这项研究中与蒽-琥珀酰亚胺杂种有关的最有希望的物质。制备最充分的候选物在表达h TLR4 / MD2的细胞系中表现出80％的单磷酰脂质A体外激动活性。