Sandbox Reserved 1701: Difference between revisions

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=== Clinical Relevance ===

[[Image:Screen Shot 2022-04-162 at 2.49.26 PM.png|420px|right|thumb|'''Figure 11.'''Schematic representation of cellular response]]

Some cells in the human body that express the MRGPRX2 receptor include mast cells in the skin, intestines, and trachea <ref name= "Porebski">PMID: 30619367</ref>. Mast cells are involved in allergic responses by their release of histamine or other inflammatory chemicals in the body. <ref name="McNeil">PMID: 25517090</ref> These responses induce common allergic reaction and anaphylaxis symptoms, such as cutaneous itching sensations or airway constriction

<ref name= "Cao" /><ref name= "Yang" /><ref name="McNeil">PMID: 25517090</ref>. Mast cells can be activated by either antibodies in the human immune response or upon ligands binding to their MRGPRX2 receptors <ref name= "McNeil" />. Ligands that bind to MRGPRX2 in the natural environment to produce an allergic response include some contents of insect venom, molecules like C48/80 or other polycationic molecules. They can also respond to endogenous signaling molecules involved in inflammation pathways and immune responses such as cytokines, anaphylatoxins, or neuropeptides <ref name= "Porebski" />. Binding to MRGPRX2 triggers an intracellular signaling pathway that eventually leads to mast cells releasing their contents containing histamine, cytokines, or other inflammatory molecules that may go on to trigger the itching sensation <ref name= "Cao" /> <ref name= "Yang" />.

Many medications commonly list chronic skin itching or inflammatory responses as side effects, such as nateglinide, an anti-diabetic drug <ref name= "Cao" />. Upon analysis of some medications that list itching as side effects such as nateglinide, they structurally share many similarities to known MRGPRX2 ligands, and could therefore initiate an unwanted itch response in patients. Other drugs such as morphine or codeine also share structural features to known MRGPRX2 ligands, which can contribute to itching side effects seen in users of these drugs <ref name= "Cao" />.

~~Because of how some~~ drugs ~~initiate an unwanted itch response~~,

[[Image:Activating_drugs.png |400px|right|thumb|'''Figure 9.''' Common prescriptions that are tied to adverse itching side effects include nateglinide, morphine, and codeine. These drugs have structural similarities to known ligands for the MRGPRX2 receptor, and can lead to MRGPRX2 activation.]]

~~MRGPRX2 has been identified~~ as ~~a potential target for drugs either involved in the inflammatory response or to mediate drugs from causing~~ an ~~unwanted reaction such~~ as [https://pubchem.ncbi.nlm.nih.gov/compound/Atracurium#section=2D-Structure Atracurium], [https://pubchem.ncbi.nlm.nih.gov/compound/441290 Rocuronium], [https://pubchem.ncbi.nlm.nih.gov/compound/2764 Ciprofloxacin], and [https://pubchem.ncbi.nlm.nih.gov/compound/149096 Levofloxacin]<ref name="Navines-Ferrer">PMID:30072729</ref>. ~~These~~ drugs have ~~similarly charged regions~~ which ~~may interact with~~ sub-pockets 1 and/~~or 2~~. ~~By binding~~ these ~~target~~ drugs, MRGPRX2 can ~~elicit~~ or ~~prevent a response to aid with itch-related side effects~~.

Many medications commonly list chronic skin itching or inflammatory responses as side effects, such as [https://pubchem.ncbi.nlm.nih.gov/compound/Nateglinide nateglinide], an anti-diabetic drug <ref name= "Cao" />. Other prescribed medications that list itching as a possible side effect are [https://pubchem.ncbi.nlm.nih.gov/compound/Atracurium#section=2D-Structure Atracurium], [https://pubchem.ncbi.nlm.nih.gov/compound/441290 Rocuronium], [https://pubchem.ncbi.nlm.nih.gov/compound/2764 Ciprofloxacin], and [https://pubchem.ncbi.nlm.nih.gov/compound/149096 Levofloxacin]<ref name="Navines-Ferrer">PMID:30072729</ref>, all of which are tied to MRGPRX2 activation.

Other drugs that have been known to trigger allergic reactions and even anaphylactic responses are opioids [https://pubchem.ncbi.nlm.nih.gov/compound/Morphine morphine] or [https://pubchem.ncbi.nlm.nih.gov/compound/5284371 codeine]<ref name= "Cao" />, which could explain anaphylactic responses to anesthetics seen in some patients<ref name="McNeil" />. Upon analysis of these drugs, they share many structural similarities that are known to bind to the sub-pockets in MRGPRX2, shown in '''Figure 9''', which is a possible explanation for the unwanted itch and inflammation responses produced in some patients when administering these drugs <ref name="McNeil" /><ref name= "Cao" />.

Possible treatments for these unwanted side effects of drugs can be developed by understanding the mechanism of the MRGPRX2 receptor. Research on Cortistatin-14, an endogenous neuropeptide ('''Figure 7'''), has shown that it has anti-inflammatory properties because of how it binds to the MRGPRX2 receptor <ref name= "Gonzalez-Rey">PMID: 16492802</ref>. Additionally, [https://pubchem.ncbi.nlm.nih.gov/compound/Osthole Osthole], an extract from [https://en.wikipedia.org/wiki/Cnidium_monnieri Cnidium monnieri plants], also known as Monnier's snow parsley, demonstrates similar MRGPRX2 inhibition because of its structural similarity to many known ligands for this receptor, and could possibly be used as a treatment option for adverse allergic reactions to commonly prescribed drugs<ref name= "Dondalska" />. More research on MRGPRX2 can open the door for the development of drugs that avoid activation of the MRGPRX2 receptor, or possible treatments for excessive inflammation and allergic reactions.

== 3D Structures ==

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@@ Line 106: / Line 106: @@
 === Clinical Relevance ===
 [[Image:Screen Shot 2022-04-162 at 2.49.26 PM.png|420px|right|thumb|'''Figure 11.'''Schematic representation of cellular response]]
-Some cells in the human body that express the MRGPRX2 receptor include mast cells in the skin, intestines, and trachea <ref name= "Porebski">PMID: 30619367</ref>. Mast cells are involved in allergic responses by their release of histamine or other inflammatory chemicals in the body. <ref name="McNeil">PMID: 25517090</ref> These responses induce common allergic reaction and anaphylaxis symptoms, such as cutaneous itching sensations or airway constriction
-<ref name= "Cao" /><ref name= "Yang" /><ref name="McNeil">PMID: 25517090</ref>. Mast cells can be activated by either antibodies in the human immune response or upon ligands binding to their MRGPRX2 receptors <ref name= "McNeil" />. Ligands that bind to MRGPRX2 in the natural environment to produce an allergic response include some contents of insect venom, molecules like C48/80 or other polycationic molecules. They can also respond to endogenous signaling molecules involved in inflammation pathways and immune responses such as cytokines, anaphylatoxins, or neuropeptides <ref name= "Porebski" />. Binding to MRGPRX2 triggers an intracellular signaling pathway that eventually leads to mast cells releasing their contents containing histamine, cytokines, or other inflammatory molecules that may go on to trigger the itching sensation <ref name= "Cao" /> <ref name= "Yang" />.
-Many medications commonly list chronic skin itching or inflammatory responses as side effects, such as nateglinide, an anti-diabetic drug <ref name= "Cao" />. Upon analysis of some medications that list itching as side effects such as nateglinide, they structurally share many similarities to known MRGPRX2 ligands, and could therefore initiate an unwanted itch response in patients. Other drugs such as morphine or codeine also share structural features to known MRGPRX2 ligands, which can contribute to itching side effects seen in users of these drugs <ref name= "Cao" />.
-Because of how some drugs initiate an unwanted itch response,
+[[Image:Activating_drugs.png |400px|right|thumb|'''Figure 9.''' Common prescriptions that are tied to adverse itching side effects include nateglinide, morphine, and codeine. These drugs have structural similarities to known ligands for the MRGPRX2 receptor, and can lead to MRGPRX2 activation.]]
-MRGPRX2 has been identified as a potential target for drugs either involved in the inflammatory response or to mediate drugs from causing an unwanted reaction such as [https://pubchem.ncbi.nlm.nih.gov/compound/Atracurium#section=2D-Structure Atracurium], [https://pubchem.ncbi.nlm.nih.gov/compound/441290 Rocuronium], [https://pubchem.ncbi.nlm.nih.gov/compound/2764 Ciprofloxacin], and [https://pubchem.ncbi.nlm.nih.gov/compound/149096 Levofloxacin]<ref name="Navines-Ferrer">PMID:30072729</ref>. These drugs have similarly charged regions which may interact with sub-pockets 1 and/or 2. By binding these target drugs, MRGPRX2 can elicit or prevent a response to aid with itch-related side effects.
+Many medications commonly list chronic skin itching or inflammatory responses as side effects, such as [https://pubchem.ncbi.nlm.nih.gov/compound/Nateglinide nateglinide], an anti-diabetic drug <ref name= "Cao" />. Other prescribed medications that list itching as a possible side effect are [https://pubchem.ncbi.nlm.nih.gov/compound/Atracurium#section=2D-Structure Atracurium], [https://pubchem.ncbi.nlm.nih.gov/compound/441290 Rocuronium], [https://pubchem.ncbi.nlm.nih.gov/compound/2764 Ciprofloxacin], and [https://pubchem.ncbi.nlm.nih.gov/compound/149096 Levofloxacin]<ref name="Navines-Ferrer">PMID:30072729</ref>, all of which are tied to MRGPRX2 activation.
+Other drugs that have been known to trigger allergic reactions and even anaphylactic responses are opioids [https://pubchem.ncbi.nlm.nih.gov/compound/Morphine morphine] or [https://pubchem.ncbi.nlm.nih.gov/compound/5284371 codeine]<ref name= "Cao" />, which could explain anaphylactic responses to anesthetics seen in some patients<ref name="McNeil" />. Upon analysis of these drugs, they share many structural similarities that are known to bind to the sub-pockets in MRGPRX2, shown in '''Figure 9''', which is a possible explanation for the unwanted itch and inflammation responses produced in some patients when administering these drugs <ref name="McNeil" /><ref name= "Cao" />.
+Possible treatments for these unwanted side effects of drugs can be developed by understanding the mechanism of the MRGPRX2 receptor. Research on Cortistatin-14, an endogenous neuropeptide ('''Figure 7'''), has shown that it has anti-inflammatory properties because of how it binds to the MRGPRX2 receptor <ref name= "Gonzalez-Rey">PMID: 16492802</ref>. Additionally, [https://pubchem.ncbi.nlm.nih.gov/compound/Osthole Osthole], an extract from [https://en.wikipedia.org/wiki/Cnidium_monnieri Cnidium monnieri plants], also known as Monnier's snow parsley, demonstrates similar MRGPRX2 inhibition because of its structural similarity to many known ligands for this receptor, and could possibly be used as a treatment option for adverse allergic reactions to commonly prescribed drugs<ref name= "Dondalska" />. More research on MRGPRX2 can open the door for the development of drugs that avoid activation of the MRGPRX2 receptor, or possible treatments for excessive inflammation and allergic reactions.
 == 3D Structures ==