Published Sep 05, 2017 on Dryad.
Cite this dataset
Schöning, Verena; Hammann, Felix; Peinl, Mark; Drewe, Jürgen (2017). Data from: Identification of any structure-specific hepatotoxic potential of different pyrrolizidine alkaloids using Random Forest and artificial Neural Network [Dataset]. Dryad. https://doi.org/10.5061/dryad.qn7d3
Pyrrolizidine alkaloids (PAs) are characteristic metabolites of some plant families and form a powerful defence mechanism against herbivores. More than 600 different PAs are known. PAs are ester alkaloids composed of a necine base and a necic acid, which can be used to divide PAs in different structural subcategories. The main target organs for PA metabolism and toxicity are liver and lungs. Additionally, PAs are potentially genotoxic, carcinogenic and exhibit developmental toxicity. Only for very few PAs, in vitro and in vivo investigations have characterised their toxic potential. However, these investigations suggest that structural differences have an influence on the toxicity of single PAs. To investigate this structural relationship for a large number of PAs, a quantitative structural-activity relationship (QSAR) analysis for hepatotoxicity of over 600 different PAs was performed, using Random Forest- and artificial Neural Networks-algorithms. These models were trained with a recently established dataset specific for acute hepatotoxicity in humans. Using this dataset, a set of molecular predictors was identified to predict the hepatotoxic potential of each compound in validated QSAR models. Based on these models, the hepatotoxic potential of the 602 PAs was predicted and the following hepatotoxic rank order in three main categories defined: (i) for necine base: otonecine > retronecine > platynecine; (ii) for necine base modification: dehydropyrrolizidine >> tertiary PA = N-oxide and (iii) for necic acid: macrocyclic diester ≥ open-ring diester > monoester. A further analysis with combined structural features revealed that necic acid has a higher influence on the acute hepatotoxicity than the necine base.
Information on the substructure search performed in PubChem to obtain the PA dataset
Applicability domain of the DILI and the PA dataset, showing the four first principal components (PC1 – PC4)