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 analysis. Third, since potential new antidepressants must distribute into brain tissues, drugs with an oral route of administration were selected and their blood-brain barrier permeability was estimated using available experimental data and in silico predictions. As a result, we identified 19 drugs, which can be potentially repurposed for the MDD treatment. These drugs belong to various therapeutic categories, including adrenergic/dopaminergic agents, antiemetics, antihistamines, antitussives, and muscle relaxants. Many of these drugs have experimentally confirmed or predicted interactions with well-known MDD-related protein targets such as monoamine (serotonin, adrenaline, dopamine) and acetylcholine receptors and transporters as well as with less trivial targets including galanin receptor type 3 (GALR3), G-protein coupled estrogen receptor 1 (GPER1), tyrosine-protein kinase JAK3, serine/threonine-protein kinase ULK1. Importantly, that the most of 19 drugs act on two or more MDD-related targets, which may produce the stronger action on gene expression changes and achieve a potent therapeutic effect. Thus, the revealed 19 drugs may represent the promising candidates for the treatment of MDD.