- #1
alfredhershey
- 3
- 0
Is it true that it should always be possible to design a competitive antagonist with higher affinity for the receptor than the affinity of any agonist?
Competitive antagonists vs any agonist
- Thread starter alfredhershey
- Start date
In summary, it is possible to find orthosteric antagonists with higher affinity than a given agonist by finding molecules that form better/additional binding interactions and/or displace "unhappy" water, resulting in a more stable complex with the receptor. However, this may not be an easy task and cannot be mathematically proven. Experiments can measure the dissociation constant of both the agonist and antagonist, but a full mathematical description of the receptor-ligand complex in a biological environment is not yet possible. Computer programs can provide estimates of affinity based on crystal structure and ligand structures, but this does not constitute a proof.
- #2
lavoisier
- 177
- 24
I don't know if I would say 'always' and 'any agonist', but it is possible to find orthosteric antagonists with higher affinity than a given agonist, why not?
E.g. if your antagonist forms better/additional binding interactions and/or displaces 'unhappy' water, it can form a more stable complex with the receptor, i.e. one with higher affinity. Not sure that it's 'easy' to find such a molecule, but I don't think anyone can prove that it's definitely not possible.
Note that the natural agonists of some receptors are not very potent, and antagonists (and agonists) with much higher affinity were found by doing drug discovery.
At least, this is what I know - if someone has better information on this, please do correct me.
E.g. if your antagonist forms better/additional binding interactions and/or displaces 'unhappy' water, it can form a more stable complex with the receptor, i.e. one with higher affinity. Not sure that it's 'easy' to find such a molecule, but I don't think anyone can prove that it's definitely not possible.
Note that the natural agonists of some receptors are not very potent, and antagonists (and agonists) with much higher affinity were found by doing drug discovery.
At least, this is what I know - if someone has better information on this, please do correct me.
- #3
alfredhershey
- 3
- 0
Sorry, forgot to add that its in the context of reversible binding. By any agonist I mean any type. By higher affinity I mean lower Kd, so I believe some equation would be involved with the answer.
Is there some sort of mathematical way to prove this?
Is there some sort of mathematical way to prove this?
- #4
lavoisier
- 177
- 24
I was indeed thinking of reversible binding, because with irreversible binding the concept of affinity has to be modified a bit.
And indeed, lower dissociation constant means greater affinity.
I'm not sure I understand what equation you're looking for. The classic pharmacology of receptor binding usually obeys a 'logistic-like' pattern.
You can read more on this here:
http://www.sciencedirect.com/science/article/pii/S1056871914002470
(article kindly suggested to me by member Stephen Tashi)
and in this thread that I actually started myself, dealing with the error in IC50 determinations:
https://www.physicsforums.com/threads/error-on-biological-assay-results.792633/
Concerning your original question, by appropriate experiments you can measure the actual dissociation constant of the agonist and of the antagonist, and from what I know, in principle there is nothing stopping Kdantagonist from being smaller than Kdagonist for at least one [agonist, antagonist] pair.
A mathematical proof... I don't think so. I guess to do that you should be able to describe your receptor-ligand complex, in a biological environment, fully and exactly by a system of equations. I may be wrong, but I don't think we're there yet. Several computer programmes are available, which take the crystal structure of a receptor and the structures of several ligands (e.g. designed by you or combinatorially), and give you estimates of their affinity for the receptor. Some of them give very good predictions, and it may be that you can say with a good confidence margin that antagonist X is likely to have a better affinity than agonist A. But I don't suppose that'd count as a proof; you would have to make the molecules and test them
And indeed, lower dissociation constant means greater affinity.
I'm not sure I understand what equation you're looking for. The classic pharmacology of receptor binding usually obeys a 'logistic-like' pattern.
You can read more on this here:
http://www.sciencedirect.com/science/article/pii/S1056871914002470
(article kindly suggested to me by member Stephen Tashi)
and in this thread that I actually started myself, dealing with the error in IC50 determinations:
https://www.physicsforums.com/threads/error-on-biological-assay-results.792633/
Concerning your original question, by appropriate experiments you can measure the actual dissociation constant of the agonist and of the antagonist, and from what I know, in principle there is nothing stopping Kdantagonist from being smaller than Kdagonist for at least one [agonist, antagonist] pair.
A mathematical proof... I don't think so. I guess to do that you should be able to describe your receptor-ligand complex, in a biological environment, fully and exactly by a system of equations. I may be wrong, but I don't think we're there yet. Several computer programmes are available, which take the crystal structure of a receptor and the structures of several ligands (e.g. designed by you or combinatorially), and give you estimates of their affinity for the receptor. Some of them give very good predictions, and it may be that you can say with a good confidence margin that antagonist X is likely to have a better affinity than agonist A. But I don't suppose that'd count as a proof; you would have to make the molecules and test them
1. What is the difference between a competitive antagonist and any agonist?
A competitive antagonist is a type of drug or molecule that binds to the same receptor as an agonist, but does not activate the receptor. This means that the antagonist blocks the agonist from binding and activating the receptor. An agonist, on the other hand, is a drug or molecule that binds to a receptor and activates it, producing a biological response.
2. How do competitive antagonists affect the activity of an agonist?
Competitive antagonists compete with agonists for binding to the same receptor. This means that the presence of a competitive antagonist can decrease the activity of an agonist by blocking its access to the receptor. The more competitive antagonists present, the less binding and activation of the receptor by the agonist will occur.
3. Can competitive antagonists be overcome by increasing the concentration of an agonist?
Yes, in most cases, increasing the concentration of an agonist can overcome the effects of a competitive antagonist. This is because increasing the concentration of the agonist allows for more molecules to bind to the receptor, increasing the chances of activation and producing a biological response despite the presence of the competitive antagonist.
4. Are there any risks associated with using competitive antagonists?
Like any other drug, competitive antagonists can have side effects and potential risks. Some common side effects may include changes in heart rate, blood pressure, or other physiological processes that are regulated by the receptor being targeted. Additionally, competitive antagonists may also interact with other drugs or substances, so it is important to consult with a healthcare professional before use.
5. Can competitive antagonists be used for therapeutic purposes?
Yes, competitive antagonists can be used for therapeutic purposes. They are commonly used in the treatment of various conditions such as hypertension, allergies, and muscle spasms. By blocking the activity of certain receptors, they can help alleviate symptoms and provide relief to patients. However, as with any drug, they should only be used under the supervision of a healthcare professional.
Similar threads
-
Biology and Medical
-
Engineering and Comp Sci Homework Help
-
Biology and Medical
Writing: Input Wanted
Captain's choices on colony ships
-
Sci-Fi Writing and World Building
-
STEM Academic Advising
-
Quantum Physics
-
Electrical Engineering
-
Introductory Physics Homework Help
-
New Member Introductions