A Deep Hydrophobic Binding Cavity is the Main Interaction for Different Y2R Antagonists. (30th November 2016)

• Record Type: Journal Article
• Authors: Burkert, Kerstin; Zellmann, Tristan; Meier, René; Kaiser, Anette; Stichel, Jan; Meiler, Jens; Mittapalli, Gopi K.; Roberts, Edward; Beck‐Sickinger, Annette G.
• Is Part Of: ChemMedChem. Volume 12:Number 1(2017)
• Page Start: 75
• Page End: 85
• Publication Date: 2016-11-30
• Subjects: antagonists -- binding models -- G protein-coupled receptors -- neuropeptide Y; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600433
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The neuropeptide Y2 receptor (Y2 R) is involved in various pathophysiological processes such as epilepsy, mood disorders, angiogenesis, and tumor growth. Therefore, the Y2 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 Y2 R in vitro and in vivo. In this study, several residues crucial to the interaction of BIIE0246 and SF‐11 derivatives with Y2 R were investigated by signal transduction assays. Using the experimental results as constraints, the antagonists were docked into a comparative structural model of the Y2 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. Abstract : Different antagonist binding sites : The binding pocket of three different Y2 R‐selective antagonists—BIIE0246, compound40, and compound46 —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 D 6.59, which is only present for BIIE0246.