title: Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes.
abstract: A new copper(II) containing bis-macrocyclic CXCR4 chemokine receptor antagonist is shown to have improved binding properties to the receptor protein in comparison to the drug AMD3100 (Plerixafor, Mozobil). The interaction of the metallodrug has been optimized by using ultrarigid chelator units that offer an equatorial site for coordination to the amino acid side chains of the protein. Binding competition assays with anti-CXCR4 antibodies show that the new compound stays bound longer and it has improved anti-HIV potency in vitro (EC(50) = 4.3 nM). X-ray structural studies using acetate as a model for carboxylate amino acid side chains indicate the nature of the coordination interaction.
authors.affiliation: Department of Chemistry and Centre for Biomedical Research, University of Hull, Hull, HU6 7RX, UK.
authors.forename: Abid
authors.initials: A
authors.lastname: Khan
authors.forename: Gary
authors.initials: G
authors.lastname: Nicholson
authors.forename: John
authors.initials: J
authors.lastname: Greenman
authors.forename: Leigh
authors.initials: L
authors.lastname: Madden
authors.forename: Graeme
authors.initials: G
authors.lastname: McRobbie
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Robert
authors.initials: R
authors.lastname: Ullom
authors.forename: Danny L
authors.initials: DL
authors.lastname: Maples
authors.forename: Randall D
authors.initials: RD
authors.lastname: Maples
authors.forename: Jon D
authors.initials: JD
authors.lastname: Silversides
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hubin
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Archibald
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D008670:Metals; D019718:Receptors, CXCR4