A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y2R Antagonists

The neuropeptide Y2 receptor (Y2R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y2R is an interesting target for drug development. A detailed understanding of the binding pocket could facilitate the development of highly selective antagonists to study the role of Y2R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF‐11 derivatives with Y2R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y2R. Despite differences in size and structure, all three antagonists display a similar binding site, including a deep hydrophobic cavity formed by transmembrane helices (TM) 4, 5, and 6, as well as a hydrophobic patch at the top of TM2 and 7. Additionally, we suggest that the antagonists block Q3.32, a position that has been shown to be crucial for binding of the amidated C terminus of NPY and thus for receptor activation. Different antagonist binding sites: The binding pocket of three different Y2R‐selective antagonists—BIIE0246, compound 40, and compound 46—were investigated. They all share an overlapping binding site with the endogenous ligand NPY and have a deep hydrophobic binding site. The important difference is the interaction with transmembrane helix 6, especially D6.59, which is only present for BIIE0246.