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Abstract
Psychedelic compounds can induce rapid-acting and
long-lasting antidepressant benefits. Understanding the
role of their hallucinatory effects is crucial for shaping
the future trajectory of antidepressant drug development.
Photoswitchable compounds targeting the 5-HT2AR offer
precise spatio-temporal control over the activation of
different downstream pathways. In this work, we
computationally discovered PQ-azo-N,N-DMT (34), a
photoswitch with improved features compared to the
previously synthesized azo-N,N-DMT (1). The new
compound shows tight binding to the 5-HT2AR, retaining all
important interactions of lysergic acid diethylamide (LSD),
exhibits positive membrane permeability, and has a strong
red-shifted absorption that would allow photocontrol in the
visible spectrum.
Supplementary materials
Title
Computational Details for Computational Design of an Improved Photoswitchable Psychedelics Based on Light Absorption, Membrane Permeation and Protein Binding
Description
Computational details of the quantum, QM/MM and molecular dynamics simulations to model the absorption spectrum, protein binding and membrane permeation of the psychedelic species.
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