Abstract
Homology modeling was performed on the N‐terminal extracellular regions of human, mouse, and guinea pig 5‐hydroxytryptamine type 3A receptors (5‐HT3R) based on the 24% sequence homology with and on the crystal structure of the snail acetylcholine binding protein (AChBP). Docking of 5‐HT3 antagonists granisetron, tropisetron, ondansetron, dolasetron ('setrons), and (+)‐tubocurarine suggests an aromatic binding cleft behind a hydrophilic vestibule. Several intra‐ and interface interactions, H‐bonds, and salt bridges stabilize the pentameric structure and the binding cleft. The planar rings of antagonists are intercalated between aromatic side‐chains (W183‐Y234, Y143‐Y153). S227 donates H‐bonds to the carbonyl groups of 'setrons. The tertiary ammonium ions interact with E236, N128 or E129, and/or W90 (cation‐π interaction). This offers a molecular explanation of the pharmacophore models of 5‐HT3R antagonists. Docking artifacts suggest some ambiguities in the binding loops A and C of the 5‐HT3AR models. Lower potencies of (+)‐tubocurarine for human, and those of tropisetron for guinea pig 5‐HT3ARs can be attributed to steric differences of I/S230 in the binding cleft and to distinct binding interactions with E229 and S227, respectively. Ligand binding interferes with crucial intra‐ and interface interactions along the binding cleft.