Membrane permeation of psychedelic tryptamines by dynamic simulations
Entity
UAM. Departamento de QuímicaPublisher
ACSDate
2024-02-20Citation
10.1021/acs.biochem.3c00598
Biochemistry 63.4 (2024): 419-428
ISSN
0006-2960 (print); 1520-4995 (online)DOI
10.1021/acs.biochem.3c00598Funded by
PID2020-117806GA-I00Project
Gobierno de España. PID2020-117806GA-I00Editor's Version
https://doi.org/10.1021/acs.biochem.3c00598Subjects
Psychedelic; 5-HT2AR; PMF; QuímicaRights
© 2024 The AuthorsAbstract
Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity
Files in this item
Google Scholar:Palmisano, Vito F.
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Agnorelli, Claudio
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Fagiolini, Andrea
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Erritzoe, David
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Nutt, David
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Faraji, Shirin
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Nogueira Pérez, Juan José
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