Kd vs IC50

 	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
   ~~~~~~~~  					 Ellen R. Laird
  ~~~~~~~~~~					 ellen &$at$& ariad.com
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