Prediction of potential adverse drug reactions utilizing highly specific structural fragments

The use of in silico approaches to assess potential adverse reactions of new pharmaceutical substances reduces the risks, financial and time costs, associated with drug development. Using our previously developed method for identifying chemical motifs associated with certain types of undesirable biological activity, we have evaluated the off-target toxicity of clinically investigated pharmaceutical substances that would help to evaluate the potential risks of further research and use in clinical practice. For this purpose, we have created highly specific structural fragments for epidermal growth factor receptor and dipeptidyl peptidase 4 inhibitors, which are two molecular targets associated with a wide range of adverse reactions. A search for compounds containing these fragments was performed among 12,070 entries with information on clinical trials in the PubChem database. We have shown that five compounds entering phase I and II trials may have an unfavorable benefit-risk ratio due to the potential inhibition of at least one of the analyzed enzymes. Incorporating such analytical frameworks into early drug discovery and preclinical assessment could substantially reduce overall development costs and timelines, facilitating the introduction of safer and more cost-effective therapeutic agents.