IC50 versus Ki

Steven A. Haney shaney at watson.princeton.edu
Thu Mar 17 08:59:26 EST 1994


In article <2m8bp8$8c6 at news.u.washington.edu>, verlinde at u.washington.edu
(Christophe Verlinde) wrote:
> 
> 
> Perhaps my question is naive but I would like to know whether
> there is in general a good correlation between Ki's and IC50's
> in enzyme inhibtion studies.
> I came across the following example in a recent SCIENCE paper,
> entitled "Rational design of potent, bioavailable, nonpeptide
> cyclic ureas as HIV protease inhibitors", Vol 263, 380-384 (1994).
> Compound  Ki(nM)  IC50(microM)  ratio
>   1       4.7     0.63          134
>   2       2.14    0.30          140
>   3       0.31    0.22          708
>   4       0.27    0.036         133
> If one omits compound 3 the correlation looks good. Compound 3 is, however,
> a serious outlier. Comments?
> Christophe Verlinde
> verlinde at gouda.bchem.washington.edu 


One thing to consider is the type of inhibition seen.  Without having read
the paper in detail, let me suggest that if compounds 1,2,4 are competitive
inhibitors, but compound 3 is a noncompetitive or uncompetitive inhibitor,
then it is possible that compound 3 can bind very tightly, but the type of
inhibition may limit its effectiveness (hence the high IC50).  There are
examples of inhibitors that when saturating the inhibitor binding site (not
the active site), the level of enzyme activity is still quite high (10-60%
of uninhibited).


Cheers,
Steve.



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