Exploring the Molecular Targets for the Antidepressant and Antisuicidal Effects of Ketamine Enantiomers by Using Network Pharmacology and Molecular Docking

Ketamine, a mixture of esketamine and arketamine, is known for rapid antidepressant and antisuicidal effects. While NMDA receptor inhibition is a key mechanism, other targets may contribute. Using computational tools, this study predicted molecular targets for each enantiomer and analyzed them with gene and network databases. Esketamine and arketamine share some targets, including NMDA receptor and phosphodiesterases 3A, 7A, and 5A, but have distinct ones: esketamine may interact with the GABAergic system, arketamine with macrophage migration inhibitory factor. Both activate neuroplasticity pathways and show addiction potential. The findings identify novel, underexplored targets possibly linked to their therapeutic effects against depression and suicide.

Study at a glance

Abstract

Ketamine, a racemic mixture of esketamine (S-ketamine) and arketamine (R-ketamine), has received particular attention for its rapid antidepressant and antisuicidal effects. NMDA receptor inhibition has been indicated as one of the main mechanisms of action of the racemic mixture, but other pharmacological targets have also been proposed. This study aimed to explore the possible multiple targets of ketamine enantiomers related to their antidepressant and antisuicidal effects. To this end, targets were predicted using Swiss Target Prediction software for each ketamine enantiomer. Targets related to depression and suicide were collected by the Gene Cards database. The intersections of targets were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Network pharmacology analysis was performed using Gene Mania and Cytoscape software. Molecular docking was used to predict the main targets of the network. The results indicated that esketamine and arketamine share some biological targets, particularly NMDA receptor and phosphodiesterases 3A, 7A, and 5A but have specific molecular targets. While esketamine is predicted to interact with the GABAergic system, arketamine may interact with macrophage migration inhibitory factor (MIF). Both ketamine enantiomers activate neuroplasticity-related signaling pathways and show addiction potential. Our results identified novel, poorly explored molecular targets that may be related to the beneficial effects of esketamine and arketamine against depression and suicide.