MFCC-DFT mapping of ligand recognition at the 5-HT2A receptor: energetic analysis of the interactions between serotonin, psychedelics, and antipsychotics.
Physical chemistry chemical physics : PCCP July 1, 2026 W S Clemente Junior, K S Bezerra, E G C Matias et al.
Depression is a major global health problem, and the serotonin 5-HT2A receptor is a key target for psychoactive drugs. This computational study examined how four ligands—serotonin, psilocybin/psilocin, LSD, and lumateperone—bind to the receptor. Using molecular fragmentation and density functional theory calculations, the total interaction energies ranged from -35.38 to -71.98 kcal/mol. Key amino acids Asp155, Phe339, Leu229, and Val366 acted as structural anchors in the binding pocket. Different parts of the ligands showed distinct interaction patterns. The findings provide a detailed energetic map of ligand recognition that may aid the rational design of new serotonergic drugs.