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

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.