Investigation of the influence of molecular structure of different organic compounds on acute toxicity towards Fathead minnow, Daphnia magna, and Tetrahymena pyriformis has been carried out using 2D simplex representation of molecular structure and two modelling methods: Random Forest (RF) and Gradient Boosting Machine (GBM). Suitable QSAR (Quantitative Structure - Activity Relationships) models were obtained. The study was focused on QSAR models interpretation. The aim of the study was to develop a set of structural fragments that simultaneously consistently increase toxicity toward Fathead minnow, Daphnia magna, Tetrahymena pyriformis. The interpretation allowed to gain more details about known toxicophores and to propose new fragments. The results obtained made it possible to rank the contributions of molecular fragments to various types of toxicity to aquatic organisms. This information can be used for molecular optimization of chemicals. According to the results of structural interpretation, the most significant common mechanisms of the toxic effect of organic compounds on Fathead minnow, Daphnia magna and Tetrahymena pyriformis are reactions of nucleophilic substitution and inhibition of oxidative phosphorylation in mitochondria. In addition acetylcholinesterase and voltage-gated ion channel of Fathead minnow and Daphnia magna are important targets for toxicants. The on-line version of the OCHEM expert system (https://ochem.eu) were used for a comparative QSAR investigation. The proposed QSAR models comply with the OECD principles and can be used to reliably predict acute toxicity of organic compounds towards Fathead minnow, Daphnia magna and Tetrahymena pyriformis with allowance for applicability domain estimation.

• Klíčová slova
• Ecotoxicity, Machine Learning, Molecular modelling, QSAR interpretation., Simplex Descriptors,
• MeSH
• acetylcholinesterasa toxicita   MeSH
• Cyprinidae * MeSH
• Daphnia chemie   MeSH
• organické látky toxicita   MeSH
• Tetrahymena pyriformis * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• organické látky MeSH

The effect of the structure of organic compounds on the acute toxicity upon oral injection in mice was studied using 2D simplex representation of the molecular structure and Random forest (RF) methods. Satisfactory quantitative structure-activity relationship (QSAR) models were constructed (R2 test = 0,61-0,62). The interpretation of the obtained QSAR models was carried out. The contributions of known toxicophores with established mechanisms of action were calculated in order to confirm the ability of the interpretation approach to correctly rank them relative to other structural fragments. The influence of the molecular surroundings of some toxicophores was analyzed. We analyzed the contributions of other highly ranked fragments from the list of common functional groups and ring systems in order to find new potential toxicophores. The on-line version of the expert system "OCHEM" (https://ochem.eu) and Arithmetic Mean Toxicity (AMT) approach were used for a comparative QSAR study.

Zavisimost' mezhdu strukturoĭ organicheskikh soedineniĭ i ostroĭ toksichnost'iu pri peroral'nom vvedenii mysham izuchali s ispol'zovaniem 2D simpleksnogo predstavleniia molekuliarnoĭ struktury i metoda “sluchaĭnogo lesa” (Random Forest, RF). Byli postroeny udovletvoritel'nye (R2 test = 0,61–0,62) modeli kolichestvennoĭ sviazi “struktura-aktivnost'” (Quantitative Structure-Activity Relationship, QSAR). Provedena interpretatsiia poluchennykh QSAR modeleĭ. Rasschitany vklady izvestnykh toksikoforov s ustanovlennymi mekhanizmami deĭstviia s tsel'iu otsenit' vozmozhnosti ikh ranzhirovaniia otnositel'no drugikh strukturnykh fragmentov. Dlia vyiavleniia novykh potentsial'nykh toksikoforov proanalizirovano vliianie molekuliarnogo okruzheniia nekotorykh toksikoforov i vklady drugikh, imeiushchikh vysokie rangi, fragmentov iz spiska obshchikh funktsional'nykh grupp i tsiklicheskikh sistem. Pri provedenii sravnitel'nogo QSAR analiza ispol'zovany onlaĭn versiia ékspertnoĭ sistemy “OCHEM” (https://ochem.eu) i algoritm AMT (Arithmetic Mean Toxicity).

• Klíčová slova
• QSAR, random forest, simplex descriptors, structural interpretation, structure-property modeling, toxicity,
• MeSH
• aplikace orální MeSH
• kvantitativní vztahy mezi strukturou a aktivitou * MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši MeSH
• organické látky toxicita   MeSH
• testy akutní toxicity * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• organické látky MeSH

We describe a novel approach of reaction representation as a combination of two mixtures: a mixture of reactants and a mixture of products. In turn, each mixture can be encoded using an earlier reported approach involving simplex descriptors (SiRMS). The feature vector representing these two mixtures results from either concatenated product and reactant descriptors or the difference between descriptors of products and reactants. This reaction representation doesn't need an explicit labeling of a reaction center. The rigorous "product-out" cross-validation (CV) strategy has been suggested. Unlike the naïve "reaction-out" CV approach based on a random selection of items, the proposed one provides with more realistic estimation of prediction accuracy for reactions resulting in novel products. The new methodology has been applied to model rate constants of E2 reactions. It has been demonstrated that the use of the fragment control domain applicability approach significantly increases prediction accuracy of the models. The models obtained with new "mixture" approach performed better than those required either explicit (Condensed Graph of Reaction) or implicit (reaction fingerprints) reaction center labeling.

• Klíčová slova
• Chemical reactions, Condensed graph of reaction, Mixtures, Rate constant prediction, Reaction fingerprints, Simplex representation of molecular structure,
• MeSH
• kinetika MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• molekulární modely * MeSH
• molekulární struktura MeSH
• organické látky chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• organické látky MeSH