# Rewiring Receptor Activation: Mechanistic Insights into Toggle Switch Modulation by 25CN-NBx Compounds

## TL;DR

This study uses simulations to show how 25CN-NBx compounds affect the 5-HT2A receptor, revealing how their structure influences receptor activation and signaling.

## Contribution

The study provides mechanistic insights into how bulky substitutions on 25CN-NBx compounds modulate the toggle switch residue W336 in the 5-HT2A receptor.

## Key findings

- Bulky substitutions on the N-benzyl ring shift the position of W336, a key toggle switch residue in the 5-HT2A receptor.
- 25CN-NB-2-OH-3-Me has the highest affinity for the 5-HT2A receptor, while 25CN-NB-2-OH-5-MeO has the lowest.
- The negative dihedral state of W336 strengthens van der Waals interactions with F332 and I163, stabilizing receptor activation.

## Abstract

The development of new treatments for neuropsychiatric
disorders
relies on a deeper understanding of the molecular mechanisms behind
psychedelic compounds, particularly how they differentiate between
hallucinogenic and antidepressant effects. In this study, we explore
by molecular dynamics simulations a series of 25CN-NBx compounds bound
to the 5-HT2A receptor. The simulations uncover that bulky
substitutions on the N-benzyl ring cause a significant
shift in the position of W336, a key toggle switch residue known to
influence receptor activation and thought to play a crucial role in
mediating psychedelic signaling. This result is confirmed through
potential of mean force calculations along the toggle switch’s
dihedral angle. End-state free energy calculations align closely with
experimental data, showing that 25CN-NB-2-OH-3-Me and 25CN-NB-2-OH-5-MeO
have the highest and lowest affinities, respectively, for the 5-HT2A receptor. Further analysis indicates that when W336 adopts
its negative dihedral state, it establishes stronger van der Waals
interactions, stabilizing its contacts with residues F332 and I163key
players previously linked to receptor activation. Our findings provide
a framework for understanding receptor activation and can be extended
to other G protein-coupled receptors where the toggle switch is central
to signal activation.