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).

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Czech Republic

Institute of Physiologically Active Compounds Russian Academy of Sciences Chernogolovka Russia

Military Institute of the Ministry of Defense Tiraspol Moldova

Citace poskytuje Crossref.org