![]() These immunoglobulins possess two identical epitope-binding regions and so are considered to be bivalent. The most common examples of bivalent ligands are the natural antibody proteins, IgE, IgG and IgD. As further expanded on below, this represents a form of ‘rebinding’. The resulting high local concentration of the dissociated pharmacophore will therefore also significantly increase its chances to bind again to its original target site. This can also lead to large increases in target residence time, because when one pharmacophore dissociates from its target site, it has to remain in ‘forced proximity’ as long as its tethered, companion pharmacophore is still bound. Indeed, binding of one pharmacophore to its corresponding site at the target brings the second pharmacophore in close proximity to that target, increasing its local concentration and thereby the probability of an interaction with the second site (Kaufman and Jain, 1992 Plückthun and Pack, 1997 Kramer and Karpen, 1998). The resulting synergy could be brought about via allosteric interactions (Valant et al., 2012), but this is not a necessary condition. This can obviously only take place when the target sites are sufficiently close together for them to be simultaneously occupied by the two pharmacophores of the ligand. This effect is commonly referred to as ‘avidity’. If a ligand is able to bind to the target via two (or more) pharmacophores, these multiple interactions can synergize to enhance the apparent affinity. In in vitro experiments, the manifestation of steep saturation curves and of accelerated dissociation in the presence of competitive ligands could mistakenly be interpreted as evidence for non-competitive, allosteric interactions.Īffinity is the term used to describe the strength of a single bimolecular interaction between a ligand and its target. This will result in lower potency than expected, although it would have significant advantages in terms of residence time. ![]() Depending on the pharmacokinetic half-life of the bivalent ligand in the body, it may not have sufficient time to achieve equilibrium with the target. These simulations shed light on two practical consequences. Also, it is only in that situation that the ligand shows increased affinity. Competitive ligands are able to interfere in a concentration-dependent manner, although much higher concentrations are required in the ‘forced proximity’ situation. Both delay the attainment of binding equilibrium (resulting in steep saturation curves) and also increase the target residence time. The present differential equation-based simulations explore the way both situations affect ligand binding. However, rebinding will also take place when the diffusion of freshly dissociated ligands is merely slowed down. This ‘forced proximity’ favours its binding and rebinding (once dissociated) to that site. This is because binding of one pharmacophore forces the second tethered one to stay close to its corresponding site. avidity) and target residence time when both pharmacophores can bind simultaneously to their target sites. Such ligands exhibit markedly increased affinity (i.e. Although the naturally occurring antibodies are predominant, it is becoming more common to combine different antibody fragments or even low molecular weight compounds to generate heterobivalent ligands. Bivalent ligands are increasingly important therapeutic agents.
0 Comments
Leave a Reply. |