Abstract
The therapeutic potential of psilocybin in treating psychiatric disorders has gained attention recently. While most research has focused on isolated psilocybin, evidence suggests that whole mushroom extracts exhibit greater efficacy, implicating a possible entourage effect of additional bioactive compounds. This study aimed to elucidate the holistic neuropharmacological effects of psilocybin-producing mushroom compounds through a computational framework incorporating network pharmacology, molecular docking, and molecular dynamics. Fifteen mushroom-derived compounds were identified from literature, of which eight exhibited favorable pharmacokinetic profiles. Target prediction and network analysis identified 44 brain-localized proteins with partial biological connectivity. Functional enrichment and pathway analyses implicate key neurological pathways. The compounds exhibited strong docking scores to neurologically relevant targets. Several compounds formed stable salt bridges with the Asp155 residue of HTR2A, mirroring serotonin’s binding behavior. Molecular dynamics simulations further confirmed high residence stability of the compounds within the binding pockets of HTR2A and MAOA. These findings support a mechanistic rationale for the enhanced efficacy of whole mushroom extracts over isolated psilocybin and underscore the therapeutic potential of other constituent compounds. The study highlights the importance of multi-target interactions in mediating neuropsychiatric effects and provides a foundation for further investigations into the synergistic roles of these compounds in CNS modulation.
Data availability
All the data is available in the public databases mentioned below: https://davidbioinformatics.nih.gov/https://www.bindingdb.org/rwd/bind/index.jsphttps://www.disgenet.org/https://string-db.org/.
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Acknowledgements
The authors acknowledge the Centre of High-Performance Computing (CHPC, www.chpc.ac.za), Cape Town, South Africa, for making computational resources available, as well as the funding provided for this research through the South African National Research Foundation (NRF) Thuthuka Programme.
Funding
This study is funded through National Research Foundation (NRF) Thuthuka programme (Grant number TTK23030380657).
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ZM: Conceptualized and designed the study. AL, JFW, and HV: writing and editing of the manuscript. MSS and EE: data curation. AN and AW: graphics design. ARI: supervised the manuscript. All authors proofread and approved the manuscript.
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Murray, Z., Lewies, A., Wentzel, J.F. et al. Network pharmacology and molecular simulation reveal the entourage effect mechanisms of psilocybin-producing mushrooms on the brain. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39483-7
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DOI: https://doi.org/10.1038/s41598-026-39483-7