Virtual test kits for predicting harmful effects triggered by drugs and chemicals mediated by specific proteins

Abstract

Poor pharmacokinetics and toxicity are not only frequent causes of late-stage failures in drug development but also a source for unnecessary animal tests. In drug discovery and for the assessment of the toxic potential of chemicals, in silico techniques are nowadays considered as valuable alternatives to in vivo approaches. Based on a receptor-modelling concept developed at our laboratory (multidimensional QSAR), we have developed and validated virtual test kits for the estrogen, androgen and aryl hydrocarbon receptor (~ endocrine disruption), for cytochrome P450 3A4 (~ metabolic transformations) and most recently for the thyroid receptor. These surrogates have been tested against a total of 430 compounds and are able to predict the binding affinity close to the experimental uncertainty. These results suggest that our approach is suited for the in silico identification of adverse effects triggered by drugs and chemicals. Consequently, we are prepared to offer a free testing to selected academic institutions and non-profit oriented organisations.