# Kd vs IC50

Greetings:
It is well known that for two compounds competing for binding
to the same protein with equilibrium dissociation constants Kd_1 and
Kd_2, the difference in the Gibbs free energy of binding is given by
ddG(2-1) = -RT ln(Kd_2/Kd_1)
It is common in the pharmaceutical industry to have assays that
generate IC50 values rather than equilibrium constants. Clearly, if
the ratio IC50_2/IC50_1 = Kd_2/Kd_1 then the IC50 ratio may be used in
the above equation.
I am requesting opinions and references on the following:
If this ratio equivalence has not been demonstrated (i.e., K_n have not
been measured in a comparable assay), is there a general relationship
that can be drawn between IC50 and Kd?
I have read a straightforward treatment of this *for enzymes* by Cheng
and Prusoff (Biochemical Pharmacology, 1973, 22, 3099 - thanks to Dr.
James Blake of Pfizer Central Research for supplying this reference);
according to their analysis, Kd for an inhibitor is equal to the IC50
only when noncompetitive or uncompetitive kinetics apply.
Their analysis assumes simple Michaelis-Menten behavior,
and begins from that equation:
V_max [S]
V_0 = -------
K_m + [S] i.e., rates of catalysis are involved
in the derivation
Unfortunately, I am dealing with binding to non-catalytic
protein domains; it is not clear to me how one could extend
the Cheng and Prusoff arguments to compounds that simply inhibit
receptor-ligand interactions.
On a related issue - it is evident from the literature that the
majority of researchers in medicinal chemistry use a direct comparison
of IC50 values as sufficient for determining the relative efficacy
among a set of inhibitors; other than a desire to validate ddG
computed by via sophisticated simulations, do computational chemists
involved in pharmaceutical research even care to consider IC50
data in terms of free energy relationships?
I'll post a summary of responses, and thanks in advance
- Ellen
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~~~~~~~~ Ellen R. Laird
~~~~~~~~~~ ellen &$at$& ariad.com
~~~~~~~~~~
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~~~~~~ARIAD Pharmaceuticals, Inc. 26 Landsdowne St.
Cambridge MA 02139
(617) 494-0400, ext 234
fax: 494-8144
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