Network pharmacology and molecular simulation reveal the entourage effect mechanisms of psilocybin-producing mushrooms on the brain

Whole mushroom extracts containing psilocybin may be more effective than isolated psilocybin for treating psychiatric disorders, possibly due to an entourage effect from additional bioactive compounds. Using computational methods including network pharmacology, molecular docking, and molecular dynamics, researchers identified fifteen compounds from psilocybin-producing mushrooms, eight with favorable pharmacokinetic profiles. Target prediction revealed 44 brain-localized proteins with biological connectivity. The compounds showed strong docking to neurological targets, with several forming stable salt bridges with the Asp155 residue of HTR2A, similar to serotonin. Molecular dynamics simulations confirmed high residence stability within HTR2A and MAOA binding pockets, supporting a mechanistic rationale for enhanced efficacy of whole mushroom extracts.

Study at a glance

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.