Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists

文献类型： 外文期刊

第一作者： Zhang, Xiaozheng

作者： Zhang, Xiaozheng;Chen, Hongqian;Zhang, Tianshu;Wang, Yibo;Wang, Xiaohui;Zhang, Xiaozheng;Yang, Kecheng;Zhang, Xiaozheng;Cui, Fengchao;Yang, Kecheng;Li, Yunqi;Jiang, Zhenyan;Rice, Kenner C.;Rice, Kenner C.;Watkins, Linda R.;Watkins, Linda R.;Hutchinson, Mark R.;Hutchinson, Mark R.;Peng, Yinghua

作者机构：

期刊名称：JOURNAL OF CHEMICAL INFORMATION AND MODELING （ 影响因子：4.956； 五年影响因子：5.39 ）

ISSN： 1549-9596

年卷期： 2018 年 58 卷 4 期

页码：

收录情况： SCI

摘要： The opioid inactive isomer (+)-naltrexone is one of the rare Toll-like receptor 4 (TLR4) antagonists with good blood-brain barrier (BBB) permeability, which is a lead with promising potential for treating neuropathic pain and drug addiction. (+)-Naltrexone targets the lipopolysaccharides (LPS) binding pocket of myeloid differentiation protein 2 (MD-2) and blocks innate immune TLR4 signaling. However, the details of the molecular interactions of (+)-naltrexone and its derivatives with MD-2 are not fully understood, which hinders the ligand-based drug discovery. Herein, in silico and in vitro assays were performed to elucidate the innate immune recognition of the opioid inactive (+)-isomers. The results showed that the conserved LPS binding pocket of MD-2 accommodated these opioid inactive (+)-isomers. The calculated binding free energies of (+)-naltrexone and its derivatives in complex with MD-2 correlated well with their experimental binding affinities and TLR4 antagonistic activities. Hydrophobic residues in the MD-2 cavity interacted directly with these (+)-naltrexone based TLR4 antagonists and principally participated in ligand binding. Increasing the hydrophobicity of substituted group at N-17 improved its TLR4 antagonistic activity, while charged groups disfavored the binding with MD-2. Molecular dynamics (MD) simulations showed the binding of (+)-naltrexone or its derivatives to MD-2 stabilized the "collapsed" conformation of MD-2, consequently blocking the binding and signaling of TLR4. Thermodynamics and dynamic analysis showed the topology of substituted group at N-17 of (+)-naltrexone affected the binding with MD-2 and TLR4 antagonistic activity. This study provides a molecular insight into the innate immune recognition of opioid inactive (+)-isomers, which would be of great help for the development of next-generation of (+)-opioid based TLR4 antagonists.

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