Editing Allosteric regulation (section)

== Pharmacology ==

Allosteric modulation of a receptor results from the binding of allosteric modulators at a different site (a "[[regulatory site]]") from that of the [[Ligand (biochemistry)|endogenous ligand]] (an "[[active site]]") and enhances or inhibits the effects of the endogenous ligand. Under normal circumstances, it acts by causing a [[conformational change]] in a receptor molecule, which results in a change in the [[Dissociation constant#Protein-ligand binding|binding affinity]] of the ligand. In this way, an allosteric ligand modulates the receptor's activation by its primary [[wikt:orthosteric|orthosteric]] ligand, and can be thought to act like a dimmer switch in an electrical circuit, adjusting the intensity of the response.

For example, the [[GABAA receptor|GABA<sub>A</sub> receptor]] has two active sites that the neurotransmitter [[gamma-aminobutyric acid]] (GABA) binds, but also has [[benzodiazepine]] and [[general anaesthetic|general anaesthetic agent]] regulatory binding sites. These regulatory sites can each produce positive allosteric modulation, [[Synergy|potentiating]] the activity of GABA. [[Diazepam]] is a [[agonist|positive allosteric modulator]] at the benzodiazepine regulatory site, and its antidote [[flumazenil]] is a [[receptor antagonist]].

More recent examples of drugs that allosterically modulate their targets include the calcium-mimicking [[cinacalcet]] and the HIV treatment [[maraviroc]].

=== Allosteric sites as drug targets ===

Allosteric proteins are involved in, and are central in many diseases,<ref name=NC>{{cite journal | vauthors = Nussinov R, Tsai C | title = Allostery in disease and in drug discovery | journal = Cell | volume = 153 | pages = 293–305 | year = 2013 | issue = 2 | pmid = 23582321 | doi = 10.1016/j.cell.2013.03.034 | doi-access = free }}</ref><ref name=AAI>{{cite journal | vauthors = Abrusan G, Ascher DB, Inouye M | title = Known allosteric proteins have central roles in genetic disease | journal = PLOS Computational Biology | volume = 18 | pages = e1009806 | year = 2022 | issue = 2 | pmid = 10138267 | doi =  10.1371/journal.pcbi.1009806 | doi-access = free | arxiv = 2107.04318 | bibcode = 2022PLSCB..18E9806A }}</ref> and allosteric sites may represent a novel [[Drug discovery#Targets|drug target]]. There are a number of advantages in using allosteric modulators as preferred therapeutic agents over classic orthosteric ligands. For example, [[G protein-coupled receptor]] (GPCR) allosteric binding sites have not faced the same evolutionary pressure as '''orthosteric sites''' to accommodate an endogenous ligand, so are more diverse.<ref name=AC>{{cite journal | vauthors = Christopoulos A, May LT, Avlani VA, Sexton PM | title = G-protein-coupled receptor allosterism: the promise and the problem(s) | journal = Biochemical Society Transactions | volume = 32 | issue = Pt 5 | pages = 873–7 | date = November 2004 | pmid = 15494038 | doi = 10.1042/BST0320873 }}</ref> Therefore, greater GPCR selectivity may be obtained by targeting allosteric sites.<ref name=AC/> This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes.<ref name=LM>{{cite journal | vauthors = May LT, Leach K, Sexton PM, Christopoulos A | title = Allosteric modulation of G protein-coupled receptors | journal = Annual Review of Pharmacology and Toxicology | volume = 47 | pages = 1–51 | year = 2007 | pmid = 17009927 | doi = 10.1146/annurev.pharmtox.47.120505.105159 }}</ref> Also, these modulators have a decreased potential for toxic effects, since modulators with limited co-operativity will have a ceiling level to their effect, irrespective of the administered dose.<ref name=AC/> Another type of pharmacological selectivity that is unique to allosteric modulators is based on co-operativity. An allosteric modulator may display neutral co-operativity with an orthosteric ligand at all subtypes of a given receptor except the subtype of interest, which is termed "absolute subtype selectivity".<ref name=LM/> If an allosteric modulator does not possess appreciable efficacy, it can provide another powerful therapeutic advantage over orthosteric ligands, namely the ability to selectively tune up or down tissue responses only when the endogenous agonist is present.<ref name=LM/>  Oligomer-specific small molecule binding sites are drug targets for medically relevant [[morpheein]]s.<ref name=pmid21643557>{{cite journal | vauthors = Jaffe EK | title = Morpheeins – A New Pathway for Allosteric Drug Discovery~!2010-02-12~!2010-05-21~!2010-06-08~! | journal = The Open Conference Proceedings Journal | volume = 1 | pages = 1–6 | year = 2010 | pmid = 21643557 | pmc = 3107518 | doi =  10.2174/2210289201001010001  |doi-access=free}}</ref>