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Determination of structural factors affecting binding to mu, kappa and delta opioid receptors.
Archives of Toxicology ( IF 6.1 ) Pub Date : 2020-02-27 , DOI: 10.1007/s00204-020-02684-8
Svetoslav Slavov 1 , William Mattes 1 , Richard D Beger 1
Affiliation  

Addiction is a complex behavioral phenomenon in which naturally occurring or synthetic chemicals modulate the response of the reward system through their binding to a variety of neuroreceptors, resulting in compulsive substance-seeking and use despite harmful consequences to the individual. Among these, the opioid receptor (OR) family and more specifically, the mu-opioid receptor (MOR) subtype plays a critical role in the addiction to powerful prescription and illicit drugs such as hydrocodone, oxycodone, fentanyl, cocaine, and methamphetamine (Contet et al. in Curr Opin Neurobiol 14(3):370-378, 2004). Conversely, agonists binding to kappa (KOR) and antagonists binding to delta opioid receptors (DOR) have been reported to induce negative reinforcing effects. As more than 700 new psychoactive substances were illegally sold between 2009 and 2016 (DEA-DCT-DIR-032-18), most of them lacking basic toxicological and pharmacological profiles, molecular modeling approaches that could quickly and reliably fill the gaps in our knowledge would be highly desirable tools for determining the effects of these synthetics. Here, we report accurate 3D-spectrometric data-activity relationship classification models for large and diverse datasets of MOR, KOR and DOR binders with areas under the receiver operating characteristic curve for the "blind" prediction sets exceeding 0.88. Structural features associated with (selective) binding to MOR, KOR and/or DOR were identified. These models could assist regulatory agencies in evaluating the health risks associated with the use of unprofiled substances as well as to help the pharmaceutical industry in its search for new drugs to combat addiction.

中文翻译:

确定影响与 mu、kappa 和 delta 阿片受体结合的结构因素。

成瘾是一种复杂的行为现象,其中天然产生的或合成的化学物质通过与多种神经受体的结合来调节奖励系统的反应,从而导致强迫性的物质寻求和使用,尽管对个体有害。其中,阿片受体 (OR) 家族,更具体地说,μ-阿片受体 (MOR) 亚型在强效处方药和非法药物(如氢可酮、羟考酮、芬太尼、可卡因和甲基苯丙胺)成瘾中起关键作用(Contet等人在 Curr Opin Neurobiol 14(3):370-378, 2004)。相反,据报道,与 kappa (KOR) 结合的激动剂和与 δ 阿片受体 (DOR) 结合的拮抗剂会诱导负强化作用。由于 2009 年至 2016 年间非法销售了 700 多种新的精神活性物质 (DEA-DCT-DIR-032-18),其中大多数缺乏基本的毒理学和药理学特征,分子建模方法可以快速可靠地填补我们的知识空白将是确定这些合成物效果的非常理想的工具。在这里,我们报告了针对 MOR、KOR 和 DOR 粘合剂的大型和多样化数据集的准确 3D 光谱数据-活动关系分类模型,其中“盲”预测集的接收者操作特征曲线下面积超过 0.88。确定了与(选择性)结合 MOR、KOR 和/或 DOR 相关的结构特征。
更新日期:2020-02-28
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