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dc.contributor.authorZachariassen, Zack George
dc.contributor.authorKarlshøj, Stefanie
dc.contributor.authorHaug, Bengt Erik
dc.contributor.authorRosenkilde, Mette M.
dc.contributor.authorVåbenø, Jon
dc.date.accessioned2016-03-08T14:08:07Z
dc.date.available2016-03-08T14:08:07Z
dc.date.issued2015-09-23
dc.description.abstractWe 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.en_US
dc.descriptionAccepted manuscript version. Published version at <a href=http://doi.org/10.1021/acs.jmedchem.5b00987>http://doi.org/10.1021/acs.jmedchem.5b00987</a>. <p>This article is part of Zach Zachariassen's doctoral thesis, which is available in Munin at <a href=http://hdl.handle.net/10037/10059>http://hdl.handle.net/10037/10059</a>en_US
dc.identifier.citationJournal of Medicinal Chemistry 2015, 58(20):8141-8153en_US
dc.identifier.cristinIDFRIDAID 1298729
dc.identifier.doi10.1021/acs.jmedchem.5b00987
dc.identifier.issn1520-4804
dc.identifier.urihttps://hdl.handle.net/10037/8776
dc.identifier.urnURN:NBN:no-uit_munin_8324
dc.language.isoengen_US
dc.rights.accessRightsopenAccess
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Legemiddelkjemi: 448en_US
dc.subjectVDP::Mathematics and natural science: 400::Chemistry: 440::Pharmaceutical chemistry: 448en_US
dc.titleProbing the molecular interactions between CXC chemokine receptor 4 (CXCR4) and an arginine-based tripeptidomimetic antagonist (KRH-1636)en_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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