Indeed, if not detoxified by GSH, electrophilic compounds can react with nucleophilic moieties within proteins and nucleic acids generating damaging covalent adducts that may cause several adverse effects such as eliciting immune responses. Its relevance in toxicity mechanisms is owed to the fact that electrophilic molecules are responsible for drug-induced liver injury, which is a very frequent cause of the withdrawal of marketed drugs, as well as of the termination of clinical studies. The conjugation with glutathione (GSH) is a well-known reaction to detoxify electrophilic compounds. The encouraging performances shown by the models developed by the MT-dataset invites to use of MetaTREE for predictive studies in the field of xenobiotic metabolism. (4) Conclusions: These results confirm that focusing on metabolic trees represents a convenient approach to increase data accuracy by reducing the false negative cases. The analysis of the applicability domain also confirms that the model based on the MT-dataset shows a more robust predictive power with a larger applicability domain. (3) Results: The comparison of the models generated by the two collected datasets reveals the better performances reached by the MT-dataset (MCC raised from 0.63 to 0.67, sensitivity from 0.56 to 0.58). After proper pre-processing, this dataset, along with the corresponding dataset extracted from MetaQSAR (MQ-dataset), was utilized to develop binary classification models using a random forest algorithm.
(2) Methods: A new metabolic database (MetaTREE) was thus collected and utilized to extract a dataset for metabolic data concerning glutathione conjugation (MT-dataset). This selection should indeed reduce the number of false negative data.
Here we aim to further increase data accuracy by focusing on publications reporting exhaustive metabolic trees. To enhance the accuracy of metabolic data, we recently proposed a manually curated database collected by a meta-analysis of the specialized literature (MetaQSAR).
(1) Background: Data accuracy plays a key role in determining the model performances and the field of metabolism prediction suffers from the lack of truly reliable data.
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