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

Bulky substitutions on the N-benzyl ring of 25CN-NBx compounds cause a significant shift in the position of W336, a key toggle switch residue in the 5-HT2A receptor. This shift influences receptor activation and is thought to play a crucial role in mediating psychedelic signaling. Potential of mean force calculations along the toggle switch's dihedral angle confirm this result. End-state free energy calculations show that 25CN-NB-2-OH-3-Me and 25CN-NB-2-OH-5-MeO have the highest and lowest affinities, respectively, for the receptor. When W336 adopts its negative dihedral state, it establishes stronger van der Waals interactions with residues F332 and I163, key players in receptor activation. This framework can extend to other G protein-coupled receptors where the toggle switch is central to signal activation.

Study at a glance

Abstract

High Resolution Image Download MS PowerPoint Slide 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-HT 2A 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-HT 2A 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.