allosteric modulation

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Allosteric modulation explained

 

Allosteric modulators are an emerging class of orally available small molecule therapeutic agents that may offer a competitive advantage over classical drugs. This potential stems from their ability to offer greater selectivity and better modulatory control at disease mediating receptors. Most marketed drugs bind receptors where the body’s own natural molecular activators (i.e. endogenous ligands) bind, specifically to a key part of each receptor’s anatomy called the “active site”. In short, most drugs must out-compete endogenous ligands in order to bind to the active site. By contrast, allosteric modulators are non-competitive because they bind receptors at a different site and modify receptor function even if the endogenous ligand also is binding. Because of this, allosteric modulators are not limited to simply turning a receptor on or off, the way most drugs are. Instead, they act more like a dimmer switch, offering control over the intensity of activation or deactivation, while allowing the body to retain its natural control over initiating receptor activation. Furthermore, with regard to the structural diversity, the allosteric approach generally affords freedom to operate – even on well-known, clinically validated targets – because the intellectual property surrounding allosteric compounds and allosteric sites is most often unexploited.

Agonists and antagonists (not shown below) compete for the same “active site” targeted by endogenous ligands.

Allosteric modulators bind, generally in the cell membrane, a non-competitive mechanism that exerts its effects on signal transduction primarily when the endogenous ligand binds at the active site.

See articles on allosteric modulation from Scientific American, In Vivo, BioWorld, The Scientist and Chemistry &Engineering News or read our white papers: Rising to the Challenge in R&D and Allosteric Modulation: a Novel Approach to Drug Discovery (published in Innovations in Pharmaceutical Technology). See also an editorial co-authored by Vincent Mutel, CEO of Addex, The Pros of Not Being Competitive published in Current Neuropharmacology, 2007, Vol. 5, No. 3.

 

Key properties & advantages of allosteric modulation

 

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  • Allosteric modulators are most influential only after the endogenous ligand is bound to the same target at the same time. By contrast, classical orthosteric drugs compete for the active site with endogenous ligands. As a result, lower affinity allosteric modulators may be effective where a similar affinity orthosteric modulator is not.
  • Allosteric modulators often are devoid of activity in the absence of endogenous ligands. Because of this, they preserve the natural biological rhythms compared to orthosteric approaches.
  • Because allosteric modulators bind on a different site compared to classical orthosteric drugs, Addex can create new chemical entities that re-address clinically validated targets – potentially offering improved therapeutic activity – without being blocked by existing intellectual property.
  • For targets where it has been difficult to make selective orthosteric drugs highly selective allosteric modulators can sometimes be identified. For example, Addex is working on orally available small molecule allosteric modulators against the GLP-1 receptor, the FSH receptor and TNF receptor – for which only peptide or hormonal therapies are available.
  • It is possible to combine allosteric modulators with orthosteric drugs. For example, a PAM could be used to potentiate an orthosteric agonist.