Predicting Uncoupling Toxicity of Organic Acids Based on Their Molecular Structure Using a Biophysical Model.,Chemical Research in Toxicology

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Predicting Uncoupling Toxicity of Organic Acids Based on Their Molecular Structure Using a Biophysical Model.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-05-28 , DOI: 10.1021/acs.chemrestox.0c00063
Andrea Ebert _{1,

2} , Kai-Uwe Goss _{1,

3}

Affiliation

We present a purely mechanistic model to predict protonophoric uncoupling activity EC_w of organic acids. All required input information can be derived from their chemical structure. This makes it a convenient predictive model to gain valuable information on the toxicity of organic chemicals already at an early stage of development of new commercial chemicals (e.g., in agriculture or pharmaceutical industries). A critical component of the model is the consideration of the possible formation of heterodimers from the neutral and anionic monomer, and its permeation through the membrane. The model was tested against literature data measured in chromatophores, submitochondrial particles, isolated mitochondria, and intact green algae cells with good success. It was also possible to reproduce pH-dependencies in isolated mitochondria and intact cells. Besides the prediction of the EC_w, the mechanistic nature of the model allows researchers to draw direct conclusions on the impact of single input factors such as pH- and voltage-gradients across the membrane, the anionic and neutral membrane permeability, and the heterodimerization constant. These insights are of importance in drug design or chemical regulation.

中文翻译：

使用生物物理模型根据其分子结构预测有机酸的解偶联毒性。

我们提出了一个纯粹的力学模型来预测质子解耦活动EC _w有机酸。所有必需的输入信息都可以从其化学结构中得出。这使得它成为一种方便的预测模型，可以在新的商业化学品开发的早期阶段（例如，在农业或制药行业中）获得有关有机化学品毒性的有价值的信息。该模型的关键组成部分是考虑由中性和阴离子单体形成异二聚体的可能性，以及其透过膜的渗透性。该模型针对在色谱仪，线粒体颗粒，分离的线粒体和完整的绿藻细胞中测得的文献数据进行了测试，取得了很好的成功。也有可能在分离的线粒体和完整细胞中重现pH依赖性。除了EC _w的预测，该模型的机械性质使研究人员可以对单个输入因素（例如跨膜的pH值和电压梯度，阴离子和中性膜的渗透性以及异二聚化常数）的影响得出直接的结论。这些见解在药物设计或化学法规中很重要。

更新日期：2020-07-20

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