HECATOS

Hepatic and Cardiac Toxicity Systems modelling

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 Obiettivo del progetto (Objective)

'HeCaToS aims at developing integrative in silico tools for predicting human liver and heart toxicity. The objective is to develop an integrated modeling framework, by combining advances in computational chemistry and systems toxicology, for modelling toxic perturbations in liver and heart across multiple scales. This framework will include vertical integrations of representations from drug(metabolite)-target interactions, through macromolecules/proteins, to (sub-)cellular functionalities and organ physiologies, and even the human whole-body level. In view of the importance of mitochondrial deregulations and of immunological dysfunctions associated with hepatic and cardiac drug-induced injuries, focus will be on these particular Adverse Outcome Pathways. Models will be populated with data from innovative in vitro 3D liver and heart assays challenged with prototypical hepato- or cardiotoxicants; data will be generated by advanced molecular and functional analytical techniques retrieving information on key (sub-)cellular toxic evens. For validating perturbed AOPs in vitro in appropriate human investigations, case studies on patients with liver injuries or cardiomyopathies due to adverse drug effects, will be developed, and biopsies will be subjected to similar analyses. Existing ChEMBL and diXa data infrastructures will be advanced for data gathering, storing and integrated statistical analysis. Model performance in toxicity prediction will be assessed by comparing in silico predictions with experimental results across a multitude of read-out parameters, which in turn will suggest additional experiments for further validating predictions. HeCaToS, organized as a private-public partnership, will generate major socioeconomic impact because it will develop better chemical safety tests leading to safer drugs, but also industrial chemicals, and cosmetics, thereby improving patient and consumer health, and sustaining EU’s industrial competitiveness.'

Introduzione (Teaser)

European scientists are working to develop a computational model to predict drug-associated toxicity.

Descrizione progetto (Article)

In most cases, market withdrawals of drugs or drug development terminations are due to liver and cardiovascular toxicity. Adverse effects can be detected even during late phases of clinical testing, or years after a drug has been introduced into the market. To prevent side effects and minimise the socioeconomic burden, we need effective tools to predict toxicity.

The EU-funded http://www.hecatos.eu/ (HECATOS) (Hepatic and cardiac toxicity systems modelling) project proposes to develop an in silico framework capable of modelling toxic perturbations in the liver and heart. This tool will integrate representations from drug-target interactions, systems toxicology and organ physiologies.

Using advanced molecular and functional analytical techniques, the consortium will obtain data on key cellular toxic events and incorporate it into the model. They will also test various toxic compounds on novel in vitro 3D liver and heart assays. Given the role of mitochondrial deregulations and immunological dysfunctions in various hepatic and cardiac drug-induced injuries, focus is on these particular pathways.

Input will also be provided from drug-treated patients and biopsy analyses using transcriptome and proteomic profiling. Comparison of in silico predictions with experimental results across a multitude of read-out parameters will validate the toxicity model and suggest further improvements.

Such an in silico approach undoubtedly offers a number of advantages over existing animal-based models for predicting drug toxicity. It should become an indispensable tool for the pharmaceutical industry that could also be applied for safety assessment of industrial chemicals and cosmetic products.