Jiangsu Key Laboratory of Chemical Pollution Control and Resources Reuse, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu Province, 210094, China.
Ministry of Environmental Protection, Nanjing Institute of Environmental Sciences, Jiang-Wang-Miao Street, Nanjing, 210042, China.
Environ Sci Pollut Res Int. 2017 Aug;24(24):20063-20071. doi: 10.1007/s11356-017-9690-1. Epub 2017 Jul 12.
Toxic chemicals entered into human body would undergo a series of metabolism, transport and excretion, and the key roles played in there processes were metabolizing enzymes, which was regulated by the pregnane X receptor (PXR). However, some chemicals in environment could activate or antagonize human pregnane X receptor, thereby leading to a disturbance of normal physiological systems. In this study, based on a larger number of 2724 structurally diverse chemicals, we developed qualitative classification models by the k-nearest neighbor method. Moreover, the logarithm of 20 and 50% effective concentrations (log EC and log EC ) was used to establish quantitative structure-activity relationship (QSAR) models. With the classification model, two descriptors were enough to establish acceptable models, with the sensitivity, specificity, and accuracy being larger than 0.7, highlighting a high classification performance of the models. With two QSAR models, the statistics parameters with the correlation coefficient (R ) of 0.702-0.749 and the cross-validation and external validation coefficient (Q ) of 0.643-0.712, this indicated that the models complied with the criteria proposed in previous studies, i.e., R > 0.6, Q > 0.5. The small root mean square error (RMSE) of 0.254-0.414 and the good consistency between observed and predicted values proved satisfactory goodness of fit, robustness, and predictive ability of the developed QSAR models. Additionally, the applicability domains were characterized by the Euclidean distance-based approach and Williams plot, and results indicated that the current models had a wide applicability domain, which especially included a few classes of environmental contaminant, those that were not included in the previous models.
有毒化学物质进入人体后会经历一系列的代谢、转运和排泄过程，在这些过程中起关键作用的是代谢酶，而这些酶又受到孕烷 X 受体（PXR）的调控。然而，环境中的一些化学物质可以激活或拮抗人体孕烷 X 受体，从而导致正常生理系统紊乱。在本研究中，我们基于大量的 2724 种结构多样的化学物质，采用 K 最近邻法建立了定性分类模型。此外，我们还使用 20%和 50%有效浓度的对数（log EC 和 log EC ）建立了定量构效关系（QSAR）模型。对于分类模型，仅使用两个描述符即可建立可接受的模型，其灵敏度、特异性和准确性均大于 0.7，这突出了模型的高分类性能。对于两个 QSAR 模型，其相关系数（R ）为 0.702-0.749，交叉验证和外部验证系数（Q ）为 0.643-0.712，这表明模型符合先前研究提出的标准，即 R > 0.6，Q > 0.5。均方根误差（RMSE）较小，为 0.254-0.414，观察值与预测值之间具有良好的一致性，这证明了所开发的 QSAR 模型具有良好的拟合度、稳健性和预测能力。此外，通过欧几里得距离法和 Williams 图来确定适用域，结果表明当前模型具有广泛的适用域，尤其是包含了环境污染物的几个类别，这些类别之前并未包含在模型中。
