Comprehensive benchmarking of computational tools for predicting toxicokinetic and physicochemical properties of chemicals

Ensuring the safety of chemicals for environmental and human health involves assessing physicochemical (PC) and toxicokinetic (TK) properties, which are crucial for absorption, distribution, metabolism, excretion, and toxicity (ADMET). Computational methods play a vital role in predicting these properties, given the current trends in reducing experimental approaches, especially those that involve animal experimentation. In the present manuscript, twelve software tools implementing Quantitative Structure–Activity Relationship (QSAR) models were selected for the prediction of 17 relevant PC and TK properties. A total of 41 validation datasets were collected from the literature, curated and used for assessing the models’ external predictivity, emphasizing the performance of the models inside the applicability domain. Overall, the results confirmed the adequate predictive performance of the majority of the selected tools, with models for PC properties (R² average = 0.717) generally outperforming those for TK properties (R² average = 0.639 for regression, average balanced accuracy = 0.780 for classification). Notably, several of the tools evaluated exhibited good predictivity across different properties and were identified as recurring optimal choices. Moreover, a systematic analysis of the chemical space covered by the external validation datasets confirmed the validity of the collected results for relevant chemical categories (e.g., drugs and industrial chemicals), further increasing the confidence in the overall evaluation. The best performing models were ultimately suggested for each investigated property and proposed as robust computational tools for high-throughput assessment of highly relevant chemical properties.

The present manuscript provides an overview of the state-of-the-art available computational tools for predicting the PC and TK properties of chemicals. The results here offer valuable guidance to researchers, regulatory authorities, and the industry in identifying robust computational tools suitable for predicting relevant chemical properties in the context of chemical design, toxicity and environmental fate assessment.