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A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y 2 R Antagonists
Author(s) -
Burkert Kerstin,
Zellmann Tristan,
Meier René,
Kaiser Anette,
Stichel Jan,
Meiler Jens,
Mittapalli Gopi K.,
Roberts Edward,
BeckSickinger Annette G.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600433
Subject(s) - hydrophobic effect , chemistry , stereochemistry , binding site , combinatorial chemistry , biochemistry
The neuropeptide Y 2 receptor (Y 2 R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y 2 R 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 Y 2 R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF‐11 derivatives with Y 2 R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y 2 R. 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 Q 3.32 , a position that has been shown to be crucial for binding of the amidated C terminus of NPY and thus for receptor activation.