Abstract
(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. To enhance the accuracy of metabolic data, we recently proposed a manually curated database collected by a meta-analysis of the specialized literature (MetaQSAR). Here we aim to further increase data accuracy by focusing on publications reporting exhaustive metabolic trees. This selection should indeed reduce the number of false negative data. (2) Methods: A new metabolic database (MetaTREE) was thus collected and utilized to extract a dataset for metabolic data concerning glutathione conjugation (MT-dataset). 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. (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). 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. (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 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.
Highlights
The conjugation with glutathione (GSH) is a well-known reaction to detoxify electrophilic compounds [1]
The data for this study were extracted from two databases internally developed: MetaQSAR and MetaTREE
The latter is a new database of metabolic trees that results from a further data selection of the MetaQSAR database, to reduce the false negative rate within the database
Summary
The conjugation with glutathione (GSH) is a well-known reaction to detoxify electrophilic compounds [1]. 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 [3]. Most of the reported predictive studies focus on the redox reactions typically catalyzed by the CYP-450 enzymes [6], while only a few predictive tools for conjugation reactions were reported in the literature [7,8]. This lack of computational studies appears to be especially relevant for both glucuronidations [8,9]
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