Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists.
Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists.
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剖析阿片类非活性异构体 ( )-纳曲酮衍生的 Toll 样受体 4 (TLR4) 拮抗剂的先天免疫识别
DOI：
10.1021/acs.jcim.7b00717
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发表时间：
2018-04-23
影响因子：
5.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Zhang X;Cui F;Chen H;Zhang T;Yang K;Wang Y;Jiang Z;Rice KC;Watkins LR;Hutchinson MR;Li Y;Peng Y;Wang X
阿片类药物（+）-纳洛酮是一种罕见的Toll样受体4（TLR 4）拮抗剂，具有良好的血脑屏障（BBB）通透性，是治疗神经病理性疼痛和药物成瘾的潜在药物。（+）-纳洛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TLR 4信号传导。然而，（+）-纳洛酮及其衍生物与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发现。在此，进行计算机模拟和体外测定以阐明阿片样物质非活性（+）-异构体的先天免疫识别。结果表明，MD-2保守的LPS结合口袋容纳了这些阿片活性（+）-异构体。计算的结合自由能与MD-2的结合亲和力和TLR 4拮抗活性相关性良好。MD-2空腔中的疏水残基与这些基于（+）-纳洛酮的TLR 4拮抗剂直接相互作用，并且主要参与配体结合。增加N-17位取代基的疏水性可提高其TLR 4拮抗活性，而带电荷基团则不利于其与MD-2的结合。分子动力学（MD）模拟显示（+）-纳洛酮或其衍生物与MD-2的结合稳定了MD-2的“塌陷”构象，从而阻断了TLR 4的结合和信号传导。热力学和动力学分析表明，（+）-纳曲酮N-17位取代基的拓扑结构影响了其与MD-2的结合和TLR 4的拮抗活性。本研究从分子水平揭示了阿片类非活性（+）-异构体的天然免疫识别机制，为开发新一代基于（+）-阿片类的TLR 4拮抗剂提供了重要的理论依据。
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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