[Nescafe]

"It is important to know that a compound with high affinity does not necessarily have high efficacy, for example an antagonist can bind with a high affinity but has no efficacy" - how so?


Potency is defined as the amount of drug required to achieve a defined biological effect.
Efficacy is defined as the maximium biological effect drug can product as a result of receptor binding.


I am a bit confused, which is important than which? Potency or efficacy?

Nescafe.

[Babcock_Hall]

I am not familiar with the formal definitions of efficacy and potency, so I will leave that to others.  However, it is probably worth distinguishing between an agonist and an antagonist with respect to receptor binding (usually in reference to a hormone or neurotransmitter).  An antagonist interferes with the the action of the agonist.  One way in which this might happen is if the antagonist binds to the receptor but does not trigger the signal transduction process that the agonist does, perhaps by not triggering the conformational change that an agonist might.

[fledarmus]

Binding affinity, efficacy, and potency are related, but they are measuring different things. Each of them is more important in particular contexts.

Binding affinity is a measure of how strongly a compound binds to an enzyme. This is measured directly by allowing a purified compound to bind to a purified enzyme. It tells you nothing about what effect the compound binding to the enzyme might have, or to how the compound gets to the enzyme in the first place. If the compound is an antagonist and it bind in the active site, then you can usually work out a correlation between the binding affinity and enzyme inhibition, but if the compound is an agonist or acts on some part of the enzyme other than the active site, the mere strength of its binding does not necessarily relate to the activity of the enzyme at all.

Efficacy is a measure of the effect on some biological property. For efficacy to be measured, you must have a working biological system in place, even if it is as simple as a transfected cell with a reporter gene. For a compound to show efficacy, it must affect the biological system, not just interact with a purified enzyme, and cells have all sorts of mechanisms and structures that might limit these possibilities. For example, if your enzyme only works inside the cell and your inhibitor can't pass through the cell membrane, it doesn't matter how strong your binding affinity is, you won't show any efficacy.

Potency is defined in a couple of ways, but always in reference to some sort of activity. You can have potency in an in vitro assay, where you are measuring the activity of an enzyme in the presence and absence of an inhibitor. A potent compound in this assay would be one in which a small amount of compound would show a large change in the measured activity of the enzyme. You can also have cell potency or in vivo potency, in which a small amount of compound will show a large change in a biological measure in the cell or the test animal respectively. It is quite common, and very exasperating, for a remarkably potent compound in vitro to show very low potency in the cell, and even more annoying for a compound to show high potency in both in vitro and cell assays but low potency in the animal. This is produced either by mechanisms that keep the test compound from reaching the enzyme that it is to inhibit, or to other biological mechanisms that counter the effect of inhibiting the enzyme.

That is a very, very broad and shallow overview of the topic. I would be happy to elaborate on any areas that you feel would be helpful.

[Babcock_Hall]

When one inhibits an enzyme by, say, 50%, that does not necessarily mean that the flux through the pathway is reduced by 50%; sometimes, it is not reduced at all (when the flux control coefficient is zero).  Metabolic control analysis is the area of biochemistry that deals with this sort of question.

[Nescafe]

Thank you for all the responses.

From a medchem point of view, would it be correct to say in drug development efficacy comes before potency? Lets say we have a compound/drug that at its early stages of development does not induce a desirable biological effect one might not want to invest time/money to evaluate/optimize its potency. I understand that it all depends on the context, but I am wondering what would be the first thing one should look at when it comes to investigating the drug potential of a compound at its early stages of development. Would it be proper to order it in such way, First, affinity of the compound for the target, second, it's maximum biological effect (efficacy), if desirable then third, the lowest concentration at which we observe a desired biological effect (potency).

Thanks =)

Nescafe.

[fledarmus]

Not exactly - it would be more accurate to say that we are looking for a compound in which all three line up predictably. If there are no confounding factors, then a compound with high binding affinity for the enzyme should also show good efficacy and potency. If a strongly binding compound does not show good efficacy, then either the enzyme isn't doing what we think it is doing in the cell, or the compound is not getting to the enzyme. If a highly efficacious compound in a cell assay does not show potency in vivo, then the compound is either being metabolized rapidly or for some other reason never makes it to the site where it can bind to the enzyme, or the body has found some other mechanism for avoiding the consequences of having the enzyme inhibited. Neither are uncommon outcomes, and both contribute very strongly to the problems and uncertainties of translating in vitro results into a possible drug.

In practice, however, enzyme binding assays are usually cheap, fast, high-throughput, and consume minute quantities of test compound. For these reasons, if it is possible to set up an enzyme assay for the system for which you are trying to develop a drug, it usually functions as the threshold for all subsequent testing of that compound. Only the most active compounds will be tested in cell assays (if they are possible), and only when compounds are found for which enzyme binding is a good predictor of cell acitivity will the best of those compounds be tested in vivo.