Repositioning of drugs for the treatment of major depressive disorder based on prediction of drug-induced gene expression changes
Abstract
Major depressive disorder (MDD) is one of the most common diseases affecting millions of people worldwide. The use of existing antidepressants in many cases does not allow achieving stable remission, probably due to insufficient understanding of pathological mechanisms. This indicates the need for the development of more effective drugs based on in-depth understanding of MDD's pathophysiology. Since the high costs and long duration of the development of new drugs, the drug repositions may be the promising alternative. In this study we have applied the recently developed DIGEP-Pred approach to identify drugs that induce changes in expression of genes associated with the etiopathogenesis of MDD, followed by identification of their potential MDD-related targets and molecular mechanisms of the antidepressive effects. The applied approach included the following steps. First, using structure-activity relationships (SARs) we predicted drug-induced gene expression changes for 3690 worldwide approved drugs. Disease enrichment analysis applied to the predicted genes allowed to identify drugs that significantly altered expression of known MDD-related genes. Second, potential drug targets, which are probable master regulators responsible for drug-induced gene expression changes, have been identified through the SAR-based prediction and network analysis. Only those drugs whose potential targets were clearly associated with MDD according to the published data, were selected for further…
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