A study of the molecular mechanism of binding kinetics and long residence times of human CCR5 receptor small molecule allosteric ligands.
David C Swinney, Paul Beavis, Kai-Ting Chuang, Yue Zheng, Ina Lee, Peter Gee, Jerome Deval, David M Rotstein, Marianna Dioszegi, Palani Ravendran, Jun Zhang, Surya Sankuratri, Rama Kondru, Georges Vauquelin
British Journal of Pharmacology | Published : 2014
BACKGROUND AND PURPOSE: The human CCR5 receptor is a co-receptor for HIV-1 infection and a target for anti-viral therapy. A greater understanding of the binding kinetics of small molecule allosteric ligand interactions with CCR5 will lead to a better understanding of the binding process and may help discover new molecules that avoid resistance. EXPERIMENTAL APPROACH: Using [(3) H] maraviroc as a radioligand, a number of different binding protocols were employed in conjunction with simulations to determine rate constants, kinetic mechanism and mutant kinetic fingerprints for wild-type and mutant human CCR5 with maraviroc, aplaviroc and vicriviroc. KEY RESULTS: Kinetic characterization of mara..View full abstract