title: Probing the Molecular Interactions between CXC Chemokine Receptor 4 (CXCR4) and an Arginine-Based Tripeptidomimetic Antagonist (KRH-1636).
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 His(113), Asp(171), Asp(262), and His(281) and also suggested the involvement of Tyr(45) and Gln(200) (potency) and Tyr(116) and Glu(288) (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 His(113) and Asp(171) and the (pyridin-2-ylmethyl)amino moiety is anchored by Asp(262) and His(281), whereas the naphthalene ring is tightly packed in a hydrophobic subpocket formed by the aromatic side chains of Trp(94), Tyr(45), and Tyr(116). The detailed picture of ligand-receptor interactions provided here will assist in structure-based design and further development of small-molecule peptidomimetic CXCR4 antagonists.
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway , Breivika, NO-9037 Tromsø, Norway.
authors.forename: Zack G
authors.initials: ZG
authors.lastname: Zachariassen
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen , Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Karlshøj
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen , Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Bengt Erik
authors.initials: BE
authors.lastname: Haug
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen , Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway , Breivika, NO-9037 Tromsø, Norway.
authors.forename: Jon
authors.initials: J
authors.lastname: Våbenø
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D008958:Models, Molecular; D008968:Molecular Conformation; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D000911:Antibodies, Monoclonal; C473941:KRH 1636; D008565:Membrane Proteins; D010455:Peptides; D011725:Pyridines; D019718:Receptors, CXCR4; D001120:Arginine; D013890:Thiourea