Effect of the structural factors of organic compounds on the acute toxicity toward Daphnia magna.

The acute toxicity of organic compounds towards Daphina magna was subjected to QSAR analysis. The two-dimensional simplex representation of molecular structure (2D SiRMS) and the support vector machine (SVM), gradient boosting (GBM) methods were used to develop QSAR models. Adequate regression QSAR models were developed for incubation of 24 h. Their interpretation allowed us to quantitatively describe and rank the well-known toxicophores, to refine their molecular surroundings, and to distinguish the structural derivatives of the fragments that significantly contribute to the acute toxicity (LC50) of organic compounds towards D. magna. Based on the results of the interpretation of the regression models, a molecular design (modification) of highly toxic compounds was performed in order to reduce their hazard. In addition, acceptable classification QSAR models were developed to reliably predict the following mode of action (MOA): specific and non-specific toxicity of organic compounds towards D. magna. When interpreting these models, we were able to determine the structural fragments and the physicochemical characteristics of molecules that are responsible for the manifestation of one of the modes of action. The on-line version of the OCHEM expert system (https://ochem.eu), HYBOT descriptors, and the random forest and SVM methods were used for a comparative QSAR investigation.

Inhibition of NADH oxidation by 1-methyl-4-phenylpyridinium analogs as the basis for the prediction of the inhibitory potency of novel compounds.

Inhibition of NADH dehydrogenase (Complex I) of the mitochondrial respiratory chain by 1-methyl-4-phenylpyridinium (MPP+) and its analogs results in dopaminergic cell death. In the present study, the inhibition of mitochondrial respiration and of NADH oxidation in inverted inner membrane preparations by the oxidation products of N-methyl-stilbazoles (N-methyl-styrylpyridiniums) are characterized. These nonflexible MPP+ analogs were found to be considerably more potent inhibitors than the corresponding MPP+ derivatives. The IC50 values for these compounds and previously published figures for MPP+ analogs were then used to select a computer model based on structural parameters to predict the inhibitory potency of other compounds that react at the "rotenone site" in Complex I. A series of 12 novel inhibitors different in structure from the basic set were used to test the predictive capacity of the models selected. Despite major structural differences between the novel test compounds and the MPP+ and styrylpyridinium analogs on which the models were based, substantial agreement was found between the predicted and experimentally determined IC50 values. The value of this technique lies in the potential for the prediction of the inhibitory potency of other drugs and toxins which block mitochondrial respiration by interacting at the rotenone sites.