MFCC–DFT mapping of ligand recognition at the 5-HT2A receptor: energetic analysis of the interactions between serotonin, psychedelics, and antipsychotics

Abstract

Mental disorders represent a major global health problem, with depression being one of the most prevalent and disabling conditions worldwide. Growing evidence suggests that the serotonergic system, particularly the 5-HT_2A receptor, plays an important role in modulating mood and cognitive processes, constituting a key pharmacological target for several psychoactive compounds. In this study, we investigated the molecular interaction profile between the 5-HT_2A receptor and four pharmacologically relevant ligands, serotonin (5-HT), psilocybin/psilocin (PSILO), lysergic acid diethylamide (LSD), and lumateperone (LMTP). Interaction energies were evaluated using the molecular fragmentation with conjugated caps (MFCC) method combined with density functional theory (DFT) calculations. Crystallographic structures were used as initial models, and residue-level interaction energies were calculated to identify the amino acids that contribute most to ligand stabilization at the receptor binding site. The results reveal that the complexes exhibit total interaction energies ranging from −35.38 to −71.98 kcal mol⁻¹ under dielectric conditions representative of the protein environment. Key residues such as Asp155, Phe339, Leu229, and Val366 were identified as the main contributors to ligand stabilization in the studied systems, highlighting their role as structural anchors within the orthosteric binding pocket. Energy decomposition further revealed distinct interaction patterns associated with different regions of the ligand. Therefore, this study provides a detailed energetic characterization of ligand recognition in the 5-HT_2A receptor and offers details that may contribute to the rational design of new serotonergic agents with potential for therapeutic applications.