Botha Michelle J, Kirton Stewart B
Department of Clinical, Pharmaceutical and Biological Science, University of Hertfordshire, Hatfield, HertfordshireAL10 9AB, United Kingdom.
ACS Omega. 2022 Oct 21;7(43):38311-38321. doi: 10.1021/acsomega.2c02714. eCollection 2022 Nov 1.
New psychoactive substances (NPS) are a group of compounds that mimic the effects of illicit substances. A range of NPS have been shown to interact with the three main classes of monoamine transporters (DAT, NET, and SERT) to differing extents, but it is unclear why these differences arise. To aid in understanding the differences in affinity between the classes of monoamine transporters, several in silico experiments were conducted. Docking experiments showed there was no direct correlation between a range of scoring functions and experimental activity, but Spearman ranking analysis showed a significant correlation (α = 0.1) for DAT, with the affinity Δ (0.42), αHB (0.40), GoldScore (0.40), and PLP (0.41) scoring functions, and for DAT (0.38) and SERT (0.40) using a consensus scoring approach. Qualitative structure-activity relationship (QSAR) experiments resulted in the generation of robust and predictive three-descriptor models for SERT ( = 0.87, = 0.8, and test set = 0.74) and DAT ( = 0.68, = 0.51, test set = 0.63). Both QSAR models described similar characteristics for binding, i.e., rigid hydrophobic molecules with a biogenic amine moiety, and were not sufficient to facilitate a deeper understanding of differences in affinity between the monoamine transporters. This contextualizes the observed promiscuity for NPS between the isoforms and highlights the difficulty in the design and development of compounds that are isoform-selective.
新型精神活性物质（NPS）是一类能够模拟非法药物作用的化合物。一系列新型精神活性物质已被证明在不同程度上与三类主要的单胺转运体（多巴胺转运体、去甲肾上腺素转运体和5-羟色胺转运体）相互作用，但尚不清楚为何会出现这些差异。为了有助于理解单胺转运体类别之间亲和力的差异，我们进行了多项计算机模拟实验。对接实验表明，一系列评分函数与实验活性之间没有直接相关性，但斯皮尔曼等级分析显示，对于多巴胺转运体，亲和力Δ（0.42）、α氢键（0.40）、GoldScore（0.40）和PLP（0.41）评分函数具有显著相关性（α = 0.1），并且使用共识评分方法时，对于多巴胺转运体（0.38）和5-羟色胺转运体（0.40）也有显著相关性。定性构效关系（QSAR）实验生成了用于5-羟色胺转运体（训练集 = 0.87，验证集 = 0.8，测试集 = 0.74）和多巴胺转运体（训练集 = 0.68，验证集 = 0.51，测试集 = 0.63）的稳健且具有预测性的三描述符模型。两个QSAR模型都描述了相似的结合特征，即具有生物胺部分的刚性疏水分子，但不足以促进对单胺转运体之间亲和力差异的更深入理解。这解释了在亚型之间观察到的新型精神活性物质的混杂性，并突出了设计和开发亚型选择性化合物的困难。
