Hello Rh Rj
Ki refers to inhibition constant, while Kd means dissociation constant. Both terms are used to describe the binding affinity that a ligand has for an enzyme or receptor.
The difference is that Kd is a more general, all-encompassing term. On the other hand, the Ki inhibition constant also represents a dissociation constant, but more narrowly for the binding of an inhibitor to an enzyme, that is, a ligand whose binding reduces the catalytic activity of the enzyme. The binding equilibrium described by the Ki value depends on the kinetic mechanism of inhibition. For instance, competitive, uncompetitive, non-competitive, and mixed inhibition.
Ki values only accurately report a binding constant when the kinetic mechanism is correctly identified. The term ‘Ki’ is used whenever this binding constant is measured through inhibition kinetics, while the term ‘Kd’ is preferred when the binding is measured more directly, for example, by fluorescence quenching, isothermal titration calorimetry, or by surface plasmon resonance.
Best.
For some covalent inhibitors, the inhibition reaction occurs in 2 steps: an equilibrium binding step followed by the formation of a covalent bond. The Ki (or Kd) measurement refers to the equilibrium binding step. The subsequent covalent reaction step is described by the inactivation rate constant kinact. The overall binding and covalent reaction process can be described by the 2nd order rate constant kinact/Ki.
To measure Ki, it is necessary to measure the effect of the inhibitor on the initial rate of the enzyme reaction before the formation of the covalent bond.
In some cases, the covalent reaction step dominates the kinetics to the extent that it is not possible to observe the equilibrium binding step. In such cases, it may only be possible to report kinact/Ki, and not separate values for kinact and Ki.
To add confusion, you will usually not see kinact/Ki reported. Instead you will see kinact/KI (upper case I versus lower case i in the subscript). They are not the same thing. KI is essentially the concentration of inhibitor that results in half the maximal rate constant of inactivation for time-dependent inhibition (kobs).
This topic and much else is covered in the book "Evaluation of Enzyme Inhibitors in Drug Discovery" by Robert A. Copeland (John Wiley & Sons, 2005).
I think it is OK to use the parameter Ki or pKi for a receptor antagonist, since it is an inhibitor.
The Kds (or pKds) of two different ligands of the same receptor can be compared as long as the measurements were made under the same conditions. The concentration ranges of the ligands used to measure their Kds may differ by necessity if the Kds are substantially different.
A complication may arise in calculating the Kd of a ligand if the Kd is close to the concentration of the receptor. This is referred to as tight binding. The simple binding equation used for measuring the Kd when it is far above the receptor concentration is not accurate for tight binding, and a different method is needed. In that case, if you are comparing two Kds you should make sure the appropriate method of measuring and calculating the Kd of the tight binder was employed.
Good question. Since the i stands for inhibition, it doesn't make sense.
By the way, I prefer to see Ki or Kd rather than pKi or pKd. It is more intuitive to understand. The only reasons to use the negative logarithms, as far as I'm concerned, are (1) to fit data on a plot where the numbers cover several orders of magnitude (good reason), or (2) to improve the linearity of a correlation plot of data that are not actually linearly related (not so good reason, left over from a time when nonlinear regression was not readily performed by desktop computers).
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