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Is there any threshold (Ki) between strong and week small molecule inhibitors? When I see the (Ki) values in any published work, how can I decide if this good or bad inhibitor?

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K$_i$ values represent the binding affinity of an inhibitor and are typically in the picomolar to micromolar (10$^{-12}$ to 10$^{-6}$ mol/L) range (ref: (a), (b)), but have also been seen as low as femtomolar values, albeit rarely (10$^{-15}$ mol/L) (ref: (c)). A small K$_i$ value (e.g. femtomolar) represents an enzyme with a high affinity, i.e. a "strong" inhibitor. But your decision of whether an inhibitor is "good or bad" or "strong" will depend on context, and how well the inhibitor fits its purpose and compares to other inhibitors. There is no standardized "threshold".

Furthermore, other factors apart from the K$_i$ value could affect how "strong" the inhibitor is. The K$_i$ value just tells you how well the inhibitor can bind to the enzyme, but other factors that affect how well the inhibitor is able to inhibit the enzyme:

  1. What type of mechanism does the inhibitor display? Competitive? Noncompetitive? Other types? Different mechanisms of binding could change qualities of the inhibitor, such as whether it is surmountable or not. Also, if the inhibition can involve binding to the enzyme-substrate complex, does this binding have a different affinity constant to K$_i$?

  2. Does the inhibitor interact with the substrate? Two inhibitors could have equal K$_i$ values but a different strength due to interactions with the substrate.

Lastly, the IC$_{50}$ is practical measure of the potency (i.e. the strength) of the inhibitor. It describes the concentration needed to inhibit enzyme activity by 50%. However, the IC$_{50}$ is dependent on the experimental conditions, such as enzyme and substrate concentrations. For some competitive inhibitors, the IC$_{50}$ may relate to the K$_i$, [S] (substrate concentration) and K$_M$ (Michaelis constant of the enzyme) with the Cheng-Prussoff equation:

$$K_i=\frac{\text{IC}_{50}}{1+\frac{[S]}{K_M}}$$

Reference K$_i$ values:
(a): Flurbiprofen at PGHS1 or PGHS2: K$_i$ = 0.5 uM to 0.6 uM
(b): Methotrexate at DHFR: K$_i$ = 7.3 pM to 2.3 nM
(c): Ribonuclease inhibitor protein at ribonuclease: K$_i$ = 1 fM.

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    $\begingroup$ Could use more explanation for context. Like, is mechanism is a type of context? $\endgroup$
    – Ryan
    Apr 5 '18 at 1:53
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    $\begingroup$ Not sure about point 2 (that the IC50 is a function of temperature). $\endgroup$
    – Ryan
    Apr 5 '18 at 1:54
  • $\begingroup$ @xusr Thanks for the (+1)! I added notes about the tight binding of femtomolar Ki inhibitors and that the IC50 is dependent on experimental conditions - I agree, it has its limitations, but it's nice to have practical models of the theory :) $\endgroup$
    – Jam
    Apr 5 '18 at 14:38

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