[D]:
Aim:
Explore the relation between efficacy and agonist binding!
This simulation allows you to explore how receptor occupancy is translated into receptor activation. The model distinguishes between receptors that are occupied by the drug but not activated (\(RD\)) and receptors that are occupied and present in the activated, responding state (\(RD^*\)). Changing the efficacy of the agonist alters how effectively receptor binding is converted into receptor activation: a high-efficacy agonist produces a larger activated fraction, whereas a low-efficacy agonist produces less activation at the same level of receptor occupancy.
Try it yourself. Change the agonist concentration and efficacy parameter and compare agonists with different efficacies while keeping their binding properties constant. Look for the following:
- Increasing agonist concentration increases receptor occupancy.
- Increasing efficacy increases the fraction of occupied receptors that enter the active state.
- A high-efficacy agonist can produce a large response with relatively modest receptor occupancy.
- A low-efficacy agonist may produce only a limited response even when receptor occupancy is high.
The first graph displays the concentration-response curve of an agonists (D) with a given efficacy (E). The fraction of responding (active) complexes [RD*] is shown in blue. The second graph displays both receptor fractions (responding (active) and bound but not responding) ([RD] + [RD*]). [RD] represents the occupied but not activated fraction and [RD*] the responding (activated) fraction. $${R + D} {\xrightleftharpoons[]{K_{D}}} RD {\xrightleftharpoons[]{E}} RD^* $$ Change the parameters of the reaction and evaluate the relation between receptor activation (efficacy) and receptor occupancy.
$${R + D} {\xrightleftharpoons[]{K_{D}}} RD\;{\xrightleftharpoons[]{E}}\;RD^* $$
µM
KD:
E:
So far, we have considered drugs mainly as either agonists, which activate receptors when they bind, or antagonists, which bind without activating them. In reality, receptor activation is often graded rather than simply “on” or “off.” Different agonists acting at the same receptor can produce different maximal responses, even when they occupy the same proportion of receptors. This difference is described by efficacy.
Efficacy refers to the ability of a receptor-bound drug to activate the receptor and generate a cellular response. It therefore describes the relationship between receptor occupancy and receptor activation. A drug with high efficacy can generate a strong response from a given level of receptor occupancy; a drug with lower efficacy produces less receptor activation at the same degree of occupancy. This distinction gives rise to two important classes of agonists:
- Full agonists have sufficient efficacy to produce the maximal response that the experimental system can generate.
- Partial agonists have lower efficacy and produce only a submaximal response, even when all available receptors are occupied.
Thus, the difference between a full and a partial agonist is not necessarily how strongly they bind to the receptor, but how effectively the drug–receptor complex produces receptor activation.
Efficacy is different from affinity
Affinity describes how strongly a drug binds to its receptor and is commonly characterized by the dissociation constant, \(K_D\). Efficacy, in contrast, describes what happens after the drug has bound: how effectively the drug–receptor complex activates the receptor and generates a response. A drug can therefore have high affinity and high efficacy, high affinity but low efficacy, or low affinity but high efficacy. Affinity determines how readily receptors become occupied; efficacy determines how effectively occupied receptors are converted into an active state. The observed maximal response of an agonist can also depend on the biological system, including receptor number and the efficiency with which receptor activation is coupled to the cellular response.
Occupancy versus activation
The model distinguishes between two populations of drug-bound receptors: \(RD\), receptors occupied by the drug but not activated, and \(RD^*\), receptors occupied by the drug and present in the activated, responding state. The total fraction of drug-bound receptors is \([RD] + [RD^*]\), whereas the activated fraction is \([RD^*]\).
This illustrates an important principle: binding to a receptor is not the same as activating it. A partial agonist may occupy a large fraction — or even essentially all — of the available receptors while producing only a limited level of receptor activation.
What should you learn from the simulation?
The key concept is that receptor occupancy and receptor response are related, but they are not identical. Drug binding determines how many receptors are occupied; drug efficacy determines how effectively those occupied receptors are converted into an active state and generate a response. This relationship explains why different agonists acting at the same receptor can produce different maximal effects.