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Probing the molecular interactions between CXC chemokine receptor 4 (CXCR4) and an arginine-based tripeptidomimetic antagonist (KRH-1636)

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https://hdl.handle.net/10037/8776
DOI
https://doi.org/10.1021/acs.jmedchem.5b00987
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accepted manuscript version (PDF)
Date
2015-09-23
Type
Journal article
Tidsskriftartikkel
Peer reviewed

Author
Zachariassen, Zack George; Karlshøj, Stefanie; Haug, Bengt Erik; Rosenkilde, Mette M.; Våbenø, Jon
Abstract
We here report an experimentally verified binding mode for the known tripeptidomimetic CXCR4 antagonist KRH-1636 (1). A limited SAR study based on the three functionalities of 1 was first conducted, followed by site-directed mutagenesis studies. The receptor mapping showed that both the potency and affinity of 1 were dependent on the transmembrane residues His113, Asp171, Asp262, and His281 and also suggested the involvement of Tyr45 and Gln200 (potency) and Tyr116 and Glu288 (affinity). Molecular docking of 1 to an X-ray structure of CXCR4 showed that the l-Arg guanidino group of 1 forms polar interactions with His113 and Asp171 and the (pyridin-2-ylmethyl)amino moiety is anchored by Asp262 and His281, whereas the naphthalene ring is tightly packed in a hydrophobic subpocket formed by the aromatic side chains of Trp94, Tyr45, and Tyr116. The detailed picture of ligand–receptor interactions provided here will assist in structure-based design and further development of small-molecule peptidomimetic CXCR4 antagonists.
Description
Accepted manuscript version. Published version at http://doi.org/10.1021/acs.jmedchem.5b00987.

This article is part of Zach Zachariassen's doctoral thesis, which is available in Munin at http://hdl.handle.net/10037/10059

Citation
Journal of Medicinal Chemistry 2015, 58(20):8141-8153
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