Binding pose depth modulates photoswitchable ligands’ efficacy at the 5-HT2A receptor
Communications Chemistry February 12, 2026 Verena Weber, Giacomo Salvadori, Federico Natale et al.
The efficacy of photoswitchable ligands for the human 5-HT2A receptor depends on the vertical depth of ligand insertion into the orthosteric binding pocket, determined by the position of a methoxy substituent. Molecular dynamics simulations show that a para-methoxy ligand (compound 1) acts as a weak antagonist in its trans form because it forms hydrogen bonds with Asp231 and Thr160, anchoring it deeper and preventing engagement with activation-critical residues. A meta-methoxy ligand (compound 2) lacks these anchoring interactions, adopts a shallower pose, and maintains agonist activity in both forms. The authors propose that ligand insertion depth is a critical determinant of efficacy, offering a framework for designing light-sensitive GPCR ligands with tunable signaling.