The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines
The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines
复制标题
DOI：
10.1016/j.scijus.2017.12.004
复制
发表时间：
2018-05-01
影响因子：
1.9
通讯作者：
Haider, Shozeb
中科院分区：
文献类型：
--
作者：
Waters, Laura;Manchester, Kieran R.;Haider, Shozeb
新型精神活性物质的非法市场正在不断扩大。苯二氮卓类药物及其衍生物是此类物质的众多类别之一，迄今为止其数量逐年增长。对于法医和临床目的来说，能够快速了解这些新出现的物质非常重要。然而，由于这些化合物的非法性质，这些“新”苯二氮卓类药物的药理学数据存在缺陷。为了进一步了解“新”苯二氮卓类药物的药理学，我们采用了定量构效关系（QSAR）方法。对一组 69 种苯二氮卓类化合物进行了分析，以开发关于已公布的 GABA(A) 受体结合值的 QSAR 训练集。 QSAR 模型返回的 R-2 值为 0.90。研究发现，影响最大的因素是两个氢键受体、两个芳香环和一个疏水基团的位置。然后选择九种随机化合物的测试集进行内部验证，以确定模型的预测能力，并将结合值与其实验数据进行比较时得出的 R-2 值为 0.86。然后使用 QSAR 模型预测 22 种苯二氮卓类药物的结合，这些药物被归类为新的精神活性物质。与冗长且昂贵的体外/体内分析相比，该模型将允许以快速且经济的方式快速预测新兴苯二氮卓类药物的结合活性。这将使法医化学家和毒理学家能够更好地了解最近开发的化合物并预测未来可能出现的物质。
The illicit market for new psychoactive substances is forever expanding. Benzodiazepines and their derivatives are one of a number of groups of these substances and thus far their number has grown year upon year. For both forensic and clinical purposes it is important to be able to rapidly understand these emerging substances. However as a consequence of the illicit nature of these compounds, there is a deficiency in the pharmacological data available for these 'new' benzodiazepines. In order to further understand the pharmacology of 'new' benzodiazepines we utilised a quantitative structure-activity relationship (QSAR) approach. A set of 69 benzodiazepine-based compounds was analysed to develop a QSAR training set with respect to published binding values to GABA(A) receptors. The QSAR model returned an R-2 value of 0.90. The most influential factors were found to be the positioning of two H-bond acceptors, two aromatic rings and a hydrophobic group. A test set of nine random compounds was then selected for internal validation to determine the predictive ability of the model and gave an R-2 value of 0.86 when comparing the binding values with their experimental data. The QSAR model was then used to predict the binding for 22 benzodiazepines that are classed as new psychoactive substances. This model will allow rapid prediction of the binding activity of emerging benzodiazepines in a rapid and economic way, compared with lengthy and expensive in vitro/in vivo analysis. This will enable forensic chemists and toxicologists to better understand both recently developed compounds and prediction of substances likely to emerge in the future.