Affinity equilibrium dissociation constant

Affinity is the strength of binding of a drag to a receptor. It is quantified by an equilibrium dissociation constant. 

Equation 6.19 predicts an increasing IC50 with either increases in L or 1. In systems with low-efficacy inverse agonists or in systems with low levels of constitutive activity, the observed location parameter is still a close estimate of the KB (equilibrium dissociation constant of the ligand-receptor complex, a molecular quantity that transcends test system type). In general, the observed potency of inverse agonists only defines the lower limit of affinity. 

This leads to the expression for the observed affinity (expressed as equilibrium dissociation constant of the ligand-receptor complex) of the modulator as... 

Aim To measure the affinity of a ligand by observing the inhibition it produces of a receptor-bound radioligand (or ligand that is traceable by other means). The object is to obtain an estimate of the equilibrium dissociation constant of the nonradioactive ligand receptor complex (alternately denoted KB or Kj. The pattern of displacement curves can also be used to determine whether or not the antagonism is competitive. 

Equilibrium (dissociation) constant, reciprocal of the association constant and affinity characterizes the binding of a molecule to a receptor. Specifically, it is the ratio of the rate of offset of the molecule away from the receptor divided by the rate of onset toward the receptor. It also is a molar concentration that binds to 50% of the receptor population. 

Kx, standard pharmacologic convention for the equilibrium dissociation constant of an agonist-receptor complex with units of M. It is the concentration that occupies half the receptor population at equilibrium. It also can be thought of as the reciprocal of affinity. 

Uncompetitive antagonism, form of inhibition (originally defined for enzyme kinetics) in which both the maximal asymptotic value of the response and the equilibrium dissociation constant of the activator (i.e., agonist) are reduced by the antagonist. This differs from noncompetitive antagonism where the affinity of the receptor for the activating drug is not altered. Uncompetitive effects can occur due to allosteric modulation of receptor activity by an allosteric modulator (see Chapter 6.4). 

Binding assays for the saxitoxins were conducted with homogenized rabbit brain and saxitoxin exchange-labelled with tritium at C-11 (92, 93). If the various saxitoxins were available with suitably intense radiolabels, then the equilibrium dissociation constant, K, could be measured directly for each. Since only saxitoxin is currently available with the necessary label, the binding experiments instead measure the ability of a compound to compete with radiolabelled saxitoxin for the binding site. The value obtained, Kj, corresponds to the uilibrium dissociation constant, K, that would be observed for the compound if it were measured directly. Affinity is defined for this assay as the reciprocal of Kj. The affinities of several of the saxitoxins (94) are summarized in Figure 11, expressed relative to saxitoxin and plotted on a logarithmic scale. 

The equilibrium dissociation constant Ks has units of molarity and its value is inversely proportional to the affinity of the substrate for the enzyme (i.e., the lower the value of Ks, the higher the affinity). The value of Ks can be readily converted to a thermodynamic free energy value by the use of the familiar Gibbs free energy equation ... 

Equations (2.10) and (2.12) are identical except for the substitution of the equilibrium dissociation constant Ks in Equation (2.10) by the kinetic constant Ku in Equation (2.12). This substitution is necessary because in the steady state treatment, rapid equilibrium assumptions no longer holds. A detailed description of the meaning of Ku, in terms of specific rate constants can be found in the texts by Copeland (2000) and Fersht (1999) and elsewhere. For our purposes it suffices to say that while Ku is not a true equilibrium constant, it can nevertheless be viewed as a measure of the relative affinity of the ES encounter complex under steady state conditions. Thus in all of the equations presented in this chapter we must substitute Ku for Ks when dealing with steady state measurements of enzyme reactions. 

Drug affinity is best quantified in terms of the equilibrium dissociation constant for these varied forms of the target enzyme. 

A noncompetitive inhibitor is one that displays binding affinity for both the free enzyme and the enzyme-substrate complex or subsequent species. In this situation the binding affinity cannot be defined by a single equilibrium dissociation constant ... 

It is a measure of the affinity of the antagonist for the receptor (the equilibrium dissociation constant). It is used to compare the potency of antagonists in a similar manner to the use of the ED50 to compare the potency of agonists. 

The protein-ligand binding affinity is usually expressed as the equilibrium dissociation constant, K, which is described by the following relationship between the concentrations of free receptor [ ], free ligand [S], and the receptor-ligand complex [ES ... 

The equilibrium dissociation constant gives a measure of the affinity of the ligand for the receptor. 

One frequently encounters the case where the equilibrium dissociation constant (iQ, see above) is defined by microconstants with Tast rates on and off the receptor. However, any change in potency in a chemical series (affinity) must represent an increase in the on (k+i) rate or a decrease in the off rate (fe i). Occasionally, either by accident or design, the off rate is altered dramatically enough to redefine the receptor kinetics of the compound such that the rates influence the actual pharmacodynam-... 

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