Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists,Journal of Chemical Information and Modeling

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Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-03-08 00:00:00 , DOI: 10.1021/acs.jcim.7b00717
Xiaozheng Zhang _{1,

2,

3} , Fengchao Cui ₄ , Hongqian Chen ₁ , Tianshu Zhang ₁ , Kecheng Yang _{2,

4} , Yibo Wang ₁ , Zhenyan Jiang ₅ , Kenner C. Rice ₆ , Linda R. Watkins ₇ , Mark R. Hutchinson ₈ , Yunqi Li ₄ , Yinghua Peng ₉ , Xiaohui Wang ₁

Affiliation

Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China
University of Chinese Academy of Sciences, Beijing, 100039, China
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
Key Laboratory of Synthetic Rubber, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China
Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20892, United States
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado 80309, United States
Discipline of Physiology, Adelaide Medical School and ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, Adelaide, South Australia 5000, Australia
State Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130112, China

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.

中文翻译：

解剖阿片类药物非活性异构体（+）-纳曲酮衍生的Toll样受体4（TLR4）拮抗剂的先天免疫识别。

阿片类药物无活性异构体（+）-纳曲酮是一种罕见的Toll样受体4（TLR4）拮抗剂，具有良好的血脑屏障（BBB）渗透性，是治疗神经性疼痛和药物成瘾的潜在先导。（+）-纳曲酮靶向髓样分化蛋白2（MD-2）的脂多糖（LPS）结合口袋，并阻断先天免疫TLR4信号传导。然而，（+）-纳曲酮及其衍生物与MD-2的分子相互作用的细节尚未完全了解，这阻碍了基于配体的药物的发现。在本文中，在计算机上和体外进行测定以阐明阿片样物质无活性（+）-异构体的先天免疫识别。结果表明，保守的MD-2 LPS结合口袋容纳了这些阿片类药物的非活性（+）异构体。（+）-纳曲酮及其衍生物与MD-2复合的计算结合自由能与它们的实验结合亲和力和TLR4拮抗活性密切相关。MD-2空腔中的疏水残基直接与这些基于（+）-纳曲酮的TLR4拮抗剂相互作用，并且主要参与配体结合。增加取代基在N-17的疏水性可改善其TLR4拮抗活性，而带电基团则不利于与MD-2的结合。分子动力学（MD）模拟显示（+）-纳曲酮或其衍生物与MD-2的结合稳定了MD-2的“塌陷”构象，从而阻断了TLR4的结合和信号传导。热力学和动力学分析表明，（+）-纳曲酮N-17处取代基的拓扑结构影响了与MD-2和TLR4拮抗活性的结合。这项研究提供了对阿片类药物无活性（+）异构体的先天免疫识别的分子洞察力，这将对下一代基于（+）-阿片类药物的TLR4拮抗剂的开发有很大帮助。

更新日期：2018-03-08

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