Spycher S, Netzeva T I, Worth A P, Escher B I
Department of Environmental Toxicology, UTOX, Swiss Federal Institute of Aquatic Science and Technology, Dübendorf, Switzerland.
SAR QSAR Environ Res. 2008;19(5-6):433-63. doi: 10.1080/10629360802348803.
A new approach for classification of uncouplers of oxidative and photophosphorylation, also suitable for screening of large chemical inventories, is introduced. Earlier fragment-based approaches for this mode of toxic action are limited to phenols but weak acids of extremely diverse chemical classes can act as uncouplers. The proposed approach overcomes the limitation to phenolic uncouplers by combining structural fragments with the global information of physico-chemical descriptors. In a top-down approach to reduce the number of candidate chemicals, firstly substructure definitions for the detection of weak acids were applied. Subsequently, conservative physico-chemical thresholds for the two most important properties for the uncoupling activity were defined: an acid dissociation constant (pK(a)) between 3 and 9, and a sufficiently low energy barrier for the internal permeability of anions (17 kcal/mol). The later was derived from a novel approach to calculate the distribution of compounds across membranes. The combination of structural and physico-chemical criteria allowed a good separation of active from inactive chemicals with high sensitivity (95%) and slightly lower (more than 75%) specificity. Applying this approach to several thousand high and low production volume chemicals retrieved a surprisingly small number of 10 compounds with a predicted excess toxicity above 10. Nevertheless, uncoupling can be an important mode of action as highlighted with several examples ranging from pesticide metabolites to persistent organic compounds.
本文介绍了一种用于氧化磷酸化和光合磷酸化解偶联剂分类的新方法，该方法也适用于筛选大量化学物质库存。早期基于片段的该毒性作用模式方法仅限于酚类，但化学类别极为多样的弱酸也可作为解偶联剂。所提出的方法通过将结构片段与物理化学描述符的全局信息相结合，克服了对酚类解偶联剂的限制。在一种自上而下减少候选化学物质数量的方法中，首先应用了用于检测弱酸的子结构定义。随后，为解偶联活性的两个最重要性质定义了保守的物理化学阈值：酸解离常数（pK(a)）在3至9之间，以及阴离子内部通透性的能量屏障足够低（17千卡/摩尔）。后者源自一种计算化合物跨膜分布的新方法。结构和物理化学标准的结合能够以高灵敏度（95%）和略低（超过75%）的特异性很好地将活性化学物质与非活性化学物质区分开来。将该方法应用于数千种高产量和低产量化学物质时，预测过量毒性高于10的化合物数量出人意料地少，仅为10种。然而，正如从农药代谢物到持久性有机化合物等几个例子所强调的那样，解偶联可能是一种重要的作用模式。
