ChemRxiv
February 7, 2023
Vito F. Palmisano, Claudio Agnorelli, David Erritzøe et al.
1 citation
Classic psychedelics target the 5-HT2A serotonin receptor, but their precise mode of action remains unclear. Computational modeling of the receptor's orthosteric binding pocket for several psychedelics—including serotonin, LSD, DMT, and a photoswitchable analog (AzoDMT)—revealed two nearly equivalent binding poses. LSD and serotonin preferred the canonical crystallized pose, whereas DMT and 4-OH-DMT slightly favored a newly identified pose. The cis form of AzoDMT was the most stable, and its azobenzene domain interacted with the same residue (L229) responsible for LSD's extracellular loop closure. These simulations clarify drug–protein interactions and may aid development of new psychedelic compounds.
Physical chemistry chemical physics : PCCP
September 18, 2025
Vito F Palmisano, Claudio Agnorelli, Shirin Faraji et al.
A new photoswitchable compound, PQ-azo-N,N-DMT, was computationally designed to improve upon an earlier version. It binds tightly to the 5-HT2A receptor, maintains key interactions similar to LSD, shows good membrane permeability, and absorbs red-shifted light for visible-spectrum photocontrol. This offers precise spatio-temporal control over receptor activation, which could help clarify the role of hallucinatory effects in antidepressant drug development.
ChemRxiv
Vito Federico Palmisano, Claudio Agnorelli, Andrea Fagiolini et al.
The ability of classic psychedelics to permeate neuronal membranes and reach intracellular 5-HT2A receptors is critical for their therapeutic effects. Using molecular dynamics simulations, this computational study examined how structural modifications to tryptamines affect membrane permeability. Dimethylation of the primary amine group and adding a methoxy group at position 5 increased permeability. In contrast, substitutions at other positions on the indole ring and protonation of the molecules raised the energy barrier at the bilayer center, making the compounds highly impermeable. These findings can guide future drug design to develop psychedelics with enhanced activity.