Identification of structural determinants of ligand selectivity in 5-HT2 receptor subtypes on the basis of protein–ligand interactions

Abstract Drug selectivity is one of the most critical improvement steps in drug development. The 5-hydroxytryptamine 2 (5-HT 2 ) receptor has 3 subtypes that exhibit different pharmacological functions. Because of their high amino acid sequence similarity, designing small molecules that selectively activate only 1 receptor among the 3 subtypes is difficult. We performed homology modeling of the 5-HT 2 receptor subtypes using the β 2 -adrenergic receptor as a template to identify differences in active sites that may influence 5-HT 2 receptor agonist selectivity. A subset of selective 5-HT 2 agonists was docked into the modeled protein structures to investigate their interactions with each receptor. Subtype-specific active site residues at positions xl2.54, 5.39, and 5.46 interacted differently with each ligand. Molecular dynamics simulations revealed that position 5.46 of the 5-HT 2A receptor interacted more favorably with selective 5-HT 2A agonists than with selective 5-HT 2B agonists. These computationally obtained insights provided clues to improving agonist selectivity for specific pharmacological action at 5-HT 2 receptors.