Computational Design of an Improved Photoswitchable Psychedelics Based on Light Absorption, Membrane Permeation and Protein Binding

14 August 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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.

Keywords

Psychedelics
Photoswitches
Protein Binding
Membrane Permeation
Photophysics
Quantum Chemistry
Molecular Dynamics
QM/MM

Supplementary materials

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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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