Avidity and positive allosteric modulation/cooperativity act hand in hand to increase the residence time of bivalent receptor ligands. doi: 10.1111/fcp.12052

Georges Vauquelin, Giampiero Bricca, Isabelle Van Liefde

    Research output: Contribution to journalArticlepeer-review

    13 Citations (Scopus)

    Abstract

    Bivalent ligands bear two target-binding pharmacophores. Their simultaneous binding increases their affinity (avidity) and residence time. They become "bitopic" when the pharmacophores 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 rate of the individual pharmacophores is 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 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).
    Original languageEnglish
    Pages (from-to)530-543
    Number of pages14
    JournalFundamental and Clinical Pharmacology
    Volume28
    Publication statusPublished - 2014

    Keywords

    • bivalent
    • bitopic
    • avidity
    • residence time
    • cooperativity
    • simulations

    Fingerprint

    Dive into the research topics of 'Avidity and positive allosteric modulation/cooperativity act hand in hand to increase the residence time of bivalent receptor ligands. doi: 10.1111/fcp.12052'. Together they form a unique fingerprint.

    Cite this