Quantum Chemical Topology and Energetic Analysis of Psychedelic and Non-Psychedelic Ligands in Coordination-Sphere Models of the Human 5-HT2A Receptor
Anaid Flores, Imelda Lizeth Lazcano-Carrasco, Mayra Lozano-Espinosa, Luis Soriano-Agueda, Carlos Z. Gómez-Castro, Marco Franco-Pérez
preprint DOI: 10.21203/rs.3.rs-11502694/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Computational chemistry study |
|---|---|
| Population | Local ligand–receptor models derived from experimental 5-HT2A structures of six ligands: serotonin, psilocin, LSD, lisuride, lumateperone and IHCH-7086 |
| Measures | QTAIM, NCI |
| Topics | Serotonin |
| Key points | Protonation increases ligand–receptor interaction energies by about 100–120 kcal/mol and separates the complexes into two regimes for which different quantum-chemical methods perform best. Protonation and model expansion mainly redistribute the strength of existing contacts centered on ASP155 rather than reorganizing the interaction network; expansion stabilizes all six complexes by −7.47 kcal/mol (serotonin) to −33.10 kcal/mol (IHCH-7086). The authors note that psilocin and LSD respond more strongly to model expansion than serotonin and lisuride, but state this does not establish a link with hallucinogenic activity. |
Abstract
Abstract Psychedelic compounds have shown promising efficacy in the treatment of psychiatric disorders, yet the electronic features of their recognition by the serotonin 2A receptor (5-HT 2A ) remain poorly characterized. Here, we present a quantum-chemical analysis of local ligand–receptor models derived from the experimental 5-HT 2A structures of six ligands: serotonin, psilocin, lysergic acid diethylamide (LSD), lisuride, lumateperone and IHCH-7086. First-sphere (4.5 Å) models were used to benchmark density-functional and MP2-based methods against DLPNO-CCSD(T) for both protonated and neutral ligands, and second-sphere (5.5 Å) models were used to evaluate the effect of extending the receptor environment. Protonation increases the interaction energies by approximately 100–120 kcal/mol and defines two interaction regimes: the range-separated hybrids ωB97X-D3 and ωB97M-V perform best for the protonated complexes, whereas RIJCOSX-SCS-MP2 BWI−DZ provides the most uniform agreement for the neutral ones. QTAIM and NCI analyses show that protonation and model expansion mainly redistribute the strength of existing contacts, centered on ASP155, rather than reorganizing the interaction network. Expansion of the model stabilizes all six complexes, with expansion energies ranging from − 7.47 kcal/mol (serotonin) to − 33.10 kcal/mol (IHCH-7086). Within the two structurally related pairs, the psychedelic ligands psilocin and LSD respond more strongly to model expansion than serotonin and lisuride, although this observation does not establish a link with hallucinogenic activity. These results illustrate how interaction energies and electron-density descriptors can be combined to characterize the local electronic environment of serotonergic ligand–receptor complexes.