μ Opioid receptor: novel antagonists and structural modeling.
μ Opioid receptor: novel antagonists and structural modeling.
复制标题
μ阿片受体：新型拮抗剂和结构建模。
DOI：
10.1038/srep21548
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发表时间：
2016-02-18
影响因子：
4.6
通讯作者：
Schuster D
中科院分区：
文献类型：
--
作者：
Kaserer T;Lantero A;Schmidhammer H;Spetea M;Schuster D
μ阿片受体（莫尔）是G蛋白偶联受体家族的重要成员，是吗啡等阿片类药物的分子靶点。尽管MOR靶向药物的历史悠久，但对受体激活或抑制后不同生物学效应的配体-受体相互作用和结构-功能关系仍知之甚少。通过解析β-funalcenamine-MOR复合物的晶体结构，我们旨在使用虚拟筛选工具，即对接，药效团和基于形状的建模来发现新的激动剂和拮抗剂。我们提出了重要的分子相互作用，活性分子共享和区分激动剂和拮抗剂。这些结果允许生成用于前瞻性虚拟筛选的理论上经验证的计算机模拟工作流程。在体外药理学试验中评价的18个虚拟命中中，三个显示拮抗剂活性，并且最活性的化合物显著抑制吗啡诱导的抗伤害感受。新鉴定的化学型有望进一步发展为研究莫尔的神经化学工具或作为潜在的治疗先导候选物。
The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.