title: Avidity and positive allosteric modulation/cooperativity act hand in hand to increase the residence time of bivalent receptor ligands.
abstract: Bivalent ligands bear two target-binding pharmacophores. Their simultaneous binding increases their affinity (avidity) and residence time. They become 'bitopic' when the binding sites at the target permit the pharmacophores the exert allosteric modulation of each other's affinity and/or activity. Present simulations reveal that positive cooperativity exacerbates these phenomena, whereas negative cooperativity curtails them, irrespective of whether the association or dissociation rates of the individual pharmacophores are affected. Positive cooperativity delays the attainment of equilibrium binding, yielding 'hemi-equilibrium' conditions and only apparent affinity constants under usual experimental conditions. Monovalent ligands that bind to one of the target sites decrease the bitopic ligand's residence time concentration-wise; their potency depends on their association rate and thereon acting cooperativity rather than on affinity. This stems from the repetitive, very fast reformation of fully bound bitopic ligand-target complexes by rebinding of freshly dissociated pharmacophores. These studies deal with kinetic binding properties (of increasing interest in pharmacology) of bitopic ligands (a promising avenue in medicinal chemistry).
authors.affiliation: Department of Molecular and Biochemical Pharmacology, Institute for Molecular Biology and Biotechnology, Free University of Brussels (VUB), Pleinlaan 2, B-1050, Brussels, Belgium.
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
authors.forename: Giampiero
authors.initials: G
authors.lastname: Bricca
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Liefde
mesh_terms: D000494:Allosteric Regulation; D006801:Humans; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: D008024:Ligands
keywords: avidity; binding kinetics; bitopic; bivalent; cooperativity; differential equations; residence time; simulations