The molecular mechanisms through which psilocybin prevents suicide: evidence from network pharmacology and molecular docking analyses

Psilocybin is among the most extensively studied psychedelics, with previous research suggesting its potential therapeutic role in suicide prevention. However, the precise mechanisms through which psilocybin may aid in suicide prevention remain unclear. This study thus employed network pharmacology and molecular docking tools to explore the mechanisms by which psilocybin may contribute to suicide prevention. Relevant drug- and disease-related targets were identified. Overlapping drug- and disease-related targets were extracted from the bioinformatics platform and imported into the STRING database to construct a protein-protein interaction (PPI) network. Key targets were selected based on topological parameters derived from network analyses conducted using Cytoscape 3.10.1. These key targets were further analyzed using GO and KEGG enrichment approaches conducted with the DAVID tool. A drug-disease-target-pathway network was subsequently constructed in Cytoscape 3.10.1. Finally, molecular docking analyses were performed to assess psilocybin's potential to interact with key targets using AutoDock Vina and the PyMOL software. A total of 46 potential targets associated with psilocybin and relevant to suicide treatment were identified, of which 13 were imported into the DAVID tool for enrichment analyses. Network analyses identified four targets-HTR2A, HTR2C, HTR7, and PRKACA-that may serve as therapeutic targets for psilocybin in suicide prevention. Enrichment analysis outcomes suggested that psilocybin may prevent suicide by modulating the serotonergic synapse and calcium signaling pathways. Molecular docking analyses revealed that HTR2A, HTR2C, HTR7, and PRKACA strongly bind to psilocybin. This study provides insights into the molecular mechanisms underlying the potential role of psilocybin in suicide prevention, offering a novel basis for further research.