I am looking for a an explanation about drug potency and how it relates to the constant Ki of that drug? Are they proportional? Is it possible for a drug to be potent yet have high Ki?
Potency is related to the effective concentration (EC50). The EC50 indicates how much of a drug is needed to achieve 50% of the maximum response. The more potent a drug, the smaller the EC50 will be. This value is obtained from a dose-response curve.
Kd is the dissociation constant and can only be obtained from a binding curve/fractional occupancy curve). In this case, Kd is the concentration of ligand needed to occupy 50% of receptors.
Ki is the inhibitor constant, but can only be obtained through calculations as seen in the attached figure.
Potency is related to the effective concentration (EC50). The EC50 indicates how much of a drug is needed to achieve 50% of the maximum response. The more potent a drug, the smaller the EC50 will be. This value is obtained from a dose-response curve.
Kd is the dissociation constant and can only be obtained from a binding curve/fractional occupancy curve). In this case, Kd is the concentration of ligand needed to occupy 50% of receptors.
Ki is the inhibitor constant, but can only be obtained through calculations as seen in the attached figure.
Hi Abbas, interesting question. I haven't looked into this but I guess that there is a tradeoff between the specificity of a drug and its affinity for a specific target.
Many monoclonal antibodies that are used to treat diseased usually have a Kd ~10e-9M.
Many antibodies target kinases. There are also small inhibitors of kinases out there that bind to these targets with much higher kD, but they are not as specific as the MoAb and inhibit housekeeping kinases as well.
Hi Abbas,
I advice to have a look on the book of Terry Kenakin 3rd edition : "A pharmacology primer". 2009.
As described in the chapter 5, efficacy and affinity can be really different in some case...
Best
Guillaume
I would say they are related. Highly potent compounds have low Ki values.
The stimulatory and inhibitory effects may overlap. Why don't you read some pharmacology of drug-receptor interaction and come back again with the question? Otherwise I just do not understand what you want to ask.
Hi Abbas. Potency is a bit of a generic term, and can be very ambiguous. Yes, you can have a "potent" compound in terms of binding, but with little pharmacological effect (e.g. an allosteric modulator of a target). Also, the "potency" of a compound in an animal is affected by many other factors (bioavailability, clearance, distribution, etc...) that have nothing to do with it's binding affinity towards its target. Hence, the terms "pharmacokinetics" (the time dependent concentration of a compound in the blood) and "pharmacodynamics" (the time dependent efficacy of a compound in an animal). In an in vitro system, potency is generally considered to be ~equivalent to the IC50/EC50/Ki of the compound, depending on the measurement.
Dear Abbas,
Unfortunately, a complete course in pharmacology is beyond this post. So, I'll make for some quick points and hope readers will pardon me for any shortcuts.
Ki and Kd are dissociation constants. Those are the values which are fully related to the affinity of your compound for your target. The lower the Ki or Kd, the stronger your ligand is on target.
Now once you move out from purely enzymatic or on-target assays there are a number of things that can modify the apparent potency or functional activity of your compound.
Just for cell-based assays, differences in mode of action, nonspecific protein binding, membrane permeability, selectivity, or competition with substrate (non-exhaustive list) are just a few of the contributions that can create discrepancies between your on-target activity and functional efficacy in cells.
Once you go in vivo, you can add on top of this list the usual absorption, distribution, metabolism and excretion issues. Plus on top of that pharmacodynamics.
So in the end, it is quite common that the best compound in terms of Ki/Kd is not the best compound in cell-based assays and/or in vivo.
Now if the discrepancy between on-target activity and functional activity gets too big you might wonder whether or not your compound works via the expected mechanism. It might just hit something else instead....
Quick afterthought....
In the past, I experienced a number of cases where the potency of a ligand against its target could vary substantially (> 1 log unit) depending on the protein / reagent supplier. This can for instance happen because of different protein constructs.
One example from literature.
Effect of construct design on MAPKAP kinase-2 activity, thermodynamic stability and ligand-binding affinity.
Arch Biochem Biophys. 2006 May 15;449(1-2):47-56.
If you have a ligand that is supposedly potent, but does not show the expected activity, just make sure that you are not facing such an artifact!
Max response may occur when only a small fraction of the receptors are occupied, so it is possible that EC50
No, Potency is related to Ki or Kd. The smaller value of the Ki or Kd the higher the potency, As ur increasing concentration of Drug-target complex.
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