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Validation of virtual test kits for predicting harmful effects triggered by drugs and chemicals
Angelo Vedani
Foundation Biographics Laboratory 3R, Friedensgasse 35, 4056 Basel, Switzerland
and Institute of Molecular Pharmacy, Department of Pharmacy, Pharmacenter,
University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
Abstract
Poor pharmacokinetics, side effects and compound toxicity are not only frequent causes of latest age failures in drug development but also a source for unnecessary animal tests. In silico techniques are nowadays considered valuable alternatives to in vivo approaches in drug discovery as well as for the assessment of the toxic potential of chemicals. Computer-based experiments can study both existing and hypothetical compounds; the methods are fast, reproducible, and typically based on human bioregulators, making the question of transferability obsolete. In the recent past, our laboratory contributed towards the development of in silico concepts (> multi-dimensional QSAR) and validated a series of “virtual test kits” based on the estrogen, androgen, thyroid, and aryl hydrocarbon receptor (endocrine disruption, receptor-mediated toxicity) as well as on the enzyme cytochrome P450 3A4 (metabolic transformations, drug-drug interactions). These test kits were trained using a representative selection of 362 substances and tested against 107 compounds different therefrom. The results suggest that our approach is suited for the in silico identification of adverse effects triggered by drugs and chemicals and encouraged us to compile an Internet Database for the virtual screening of drugs and chemicals for toxic effects. The PhD thesis is aimed at an extended validation of the existing test kits including 200–500 new compounds and the setup of the computational protocols enabling access of the pilot project to trustworthy institutions.
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Validation of virtual test kits for predicting harmful effects triggered by drugs and chemicals
Angelo Vedani
Foundation Biographics Laboratory 3R, Friedensgasse 35, 4056 Basel, Switzerland, and Institute of Molecular Pharmacy, Department of Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland, www.biograf.ch
Abstract
Poor pharmacokinetics, side effects and compound toxicity are not only frequent causes of latest age failures in drug development but also a source for unnecessary animal tests. In silico techniques are nowadays considered valuable alternatives to in vivo approaches in drug discovery as well as for the assessment of the toxic potential of chemicals. Computer-based experiments can study both existing and hypothetical compounds; the methods are fast, reproducible, and typically based on human bioregulators, making the question of transferability obsolete. In the recent past, our laboratory contributed towards the development of in silico concepts (> multi-dimensional QSAR) and validated a series of “virtual test kits” based on the estrogen, androgen, thyroid, and aryl hydrocarbon receptor (endocrine disruption, receptor-mediated toxicity) as well as on the enzyme cytochrome P450 3A4 (metabolic transformations, drug-drug interactions). These test kits were trained using a representative selection of 362 substances and tested against 107 compounds different therefrom. The results suggest that our approach is suited for the in silico identification of adverse effects triggered by drugs and chemicals and encouraged us to compile an Internet Database for the virtual screening of drugs and chemicals for toxic effects. The PhD thesis is aimed at an extended validation of the existing test kits including 200–500 new compounds and the setup of the computational protocols enabling access of the pilot project to trustworthy institutions.
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