Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultrarigid metal complexes
Khan, Abid × Nicholson, Gary Greenman, John Madden, Leigh McRobbie, Graeme Pannecouque, Christophe De Clercq, Erik Ullom, Robert Maples, Danny L Maples, Randall D Silversides, Jon D Hubin, Timothy J Archibald, Stephen J #
American Chemical Society
Journal of the American Chemical Society vol:131 issue:10 pages:3416-3417
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.