Metatox - Web application for generation of metabolic pathways and toxicity estimation

Abstract

Xenobiotics biotransformation in humans is a process of the chemical modifications, which may lead to the formation of toxic metabolites. The prediction of such metabolites is very important for drug development and ecotoxicology studies. We created the web-application MetaTox ( http://way2drug.com/mg ) for the generation of xenobiotics metabolic pathways in the human organism. For each generated metabolite, the estimations of the acute toxicity (based on GUSAR software prediction), organ-specific carcinogenicity and adverse effects (based on PASS software prediction) are performed. Generation of metabolites by MetaTox is based on the fragments datasets, which describe transformations of substrates structures to a metabolites structure. We added three new classes of biotransformation reactions: Dehydrogenation, Glutathionation, and Hydrolysis, and now metabolite generation for 15 most frequent classes of xenobiotic’s biotransformation reactions are available. MetaTox calculates the probability of formation of generated metabolite — it is the integrated assessment of the biotransformation reactions probabilities and their sites using the algorithm of PASS ( http://way2drug.com/passonline ). The prediction accuracy estimated by the leave-one-out cross-validation (LOO-CV) procedure calculated separately for the probabilities of biotransformation reactions and their sites is about 0.9 on the average for all reactions.

MetaTox 2.0: Estimating the Biological Activity Spectra of Drug-like Compounds Taking into Account Probable Biotransformations

“…The algorithm, which is implemented in MetaTox 2.0 for the generation and assessment of metabolites, remained the same as that published earlier . MetaTox 2.0 generates metabolites for 19 biotransformation reactions (the first version of MetaTox predicted nine biotransformation reactions, its update in the year 2019 included 15 biotransformation reactions). A complete list of MetaTox biotransformation reactions and their characteristics in the training set are represented in Table .…”

“…A complete list of MetaTox biotransformation reactions and their characteristics in the training set are represented in Table . The reactions that were added compared to the publication of Rudik with coauthors are bolded. The training sets for the models predicting the previously published biotransformation reactions were also updated.…”

GLORYx: Prediction of the Metabolites Resulting from Phase 1 and Phase 2 Biotransformations of Xenobiotics

“…There are several other metabolite prediction tools, both commercial (e.g., ADMET Predictor 18 from SimulationsPlus, StarDrop 19 from Optibrium, and MetaSite from Molecular Discovery 20 ) and freely available (e.g., MetaTox 13 , 14 ), that incorporate SoM prediction into their metabolite prediction approaches. These tools either focus solely on CYP-mediated metabolism, have not been published, or, as described above for MetaTox, have been evaluated in such a way that makes it difficult to determine how well the metabolite structures themselves were predicted.…”

“…A further freely available tool, MetaTox, , predicts metabolites by separately predicting the probability that each potential reaction class is relevant to the given molecule and also predicting the probability of a reaction occurring at each possible reaction center given each possible reaction class. The probability that the resulting metabolite is formed is calculated by combining both of these probabilities, which can then be used to rank the predictions.…”

“…The reaction types include both phase 1 and phase 2 reaction types, though it is unclear how many reaction rules there are in total. During leave-one-out cross-validation, MetaTox obtained invariant accuracy prediction (IAP, a metric related to area under the receiver operating characteristic curve (AUC)) values between 0.79 and 0.95 for the prediction of the correct reaction class and IAP values between 0.86 and 0.99 for the prediction of the reacting atoms for each of the biotransformation classes …”