Avermectins have been effectively used in medicine, veterinary medicine, and agriculture as antiparasitic agents for many years. However, there are still no reliable data on the main ecotoxicological characteristics of most individual avermectins. Although many QSAR models have been proposed to describe the acute toxicity of organic compounds towards Tetrahymena pyriformis (T. pyriformis), avermectins are outside the applicability domain of these models. The influence of the molecular structures of various organic compounds on the acute toxicity towards T. pyriformis was studied using the OCHEM web platform (https://ochem.eu). A data set of 1792 toxicants was used to create models. The QSAR (Quantitative Structure-Activity Relationship) models were developed using the molecular descriptors Dragon, ISIDA, CDK, PyDescriptor, alvaDesc, and SIRMS and machine learning methods, such as Least Squares Support Vector Machine and Transformer Convolutional Neural Network. The HYBOT descriptors and Random Forest were used for a comparative QSAR investigation. Since the best predictive ability was demonstrated by the Transformer Convolutional Neural Network model, it was used to predict the toxicity of individual avermectins towards T. pyriformis. During a structural interpretation of the developed QSAR model, we determined the significant molecular transformations that increase and decrease the acute toxicity of organic compounds.

Histone deacetylase inhibitors represent the most important class of drugs for the treatment of human cancer and other diseases due to their influence on cell growth, differentiation, and apoptosis. Among the well-known eighteen histone deacetylases, histone deacetylase 6 (HDAC6), which is involved in oncogenesis, cell survival, and cancer cell metastasis, is of great importance. Using the CDK and alvaDesc molecular descriptors and the Random Forest and EXtreme Gradient Boosting methods, we propose a number of adequate QSAR classification models, which are integrated into a consensus model and are freely available on the OCHEM web platform (https://ochem.eu). The consensus QSAR model is used for virtual screening of a series of seven new compounds, the derivatives of N-((hydroxyamino)-oxoalkyl)-2-(quinazoline-4-ilamino)-benzamides, the synthesis schemes of which are also presented in this work. In vitro evaluation of the inhibitory activity (IC₅₀) of this series of compounds against HDAC6 allowed us to confirm the results of virtual screening and to reveal promising compounds V-2 and V-4, IC₅₀ of which is 3.25 nM and 0.04 nM, respectively. The subsequent in silico evaluation of the main ADMET properties of active compounds V-2 and V-4 allowed us to find that they have acceptable pharmacokinetic parameters and level of acute toxicity.

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.