iSafeRat Mechanisms of toxic action profiler

The aim of this profiler is to categorize chemicals according to their mechanisms of toxic action (MechoAs) in different species (including various mammals, fish, invertebrates, algae, fungi etc.). MechoAs include molecular initiating events (MIE) and in some cases, some subsequent molecular events (e.g. metabolism as MIE and subsequent molecular events for the metabolites). As such, it is useful for any toxicity or ecotoxicity endpoint that involves systemic toxicity (for instance chronic toxicity to fish or acute oral toxicity to rats).
The profiler was developed on a basis of experimental mechanistic studies (mainly on rats and fish), comparison of experimental ecotoxicity values with high accuracy QSAR results for different MechoAs, examination of structures using chemistry knowledge.
The profiler was developed from a dataset of more than 1800 molecules, for which data has been extracted from more than 350 publications.
Reference source:
For MechoA scheme v1.0 methods, results and datasets: Bauer, F.J.; Thomas, P.C.; Fouchard, S.Y.; Neunlist, S.J.M. Comput.Toxicol., 2018, 7, 36-45
For MechoA scheme v2.0 and further versions: not published yet.

General MechoAs generic description:

1. Membrane destabilization: accumulation of molecules in cell membranes without specific reaction
2. Enzymatic hydrolysis: a mixture of both direct accumulation and enzymatic hydrolysis generating acidity
3. Reactive toxicity: spontaneous non-enzymatic reactions with endogenous compounds (proteins, DNA)
4. Pro-active toxicity: metabolic transformation of the molecule into compounds with different biological activities (e.g. into reactive compounds, or into inhibitors of enzymes)
5. Indirect enzyme disruption: modification of the environment of an enzyme, preventing its normal activity
6. Direct docking interaction: binding to a docking site of a key protein (enzyme, receptor, ion channel)