allosteric modulation
Allosteric, literally translated from its Greek roots, means: other site. Thus, allosteric modulators bind receptors at sites that are distinct from the binding sites used by classical drugs as well as the body's own natural “endogenous” ligands. Because of this Addex believes allosteric modulation may offer more sophisticated ways to normalize biological signaling perturbed by disease compared to small molecule “orthosteric” agonist and antagonist drugs.
See our white paper, Allosteric Modulation: a Novel Approach to Drug Discovery, recently published in Innovations in Pharmaceutical Technology 24, pp22-26, 2007 and 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.
Some key advantages
• Allosteric modulators do not compete with endogenous ligands and therefore can exert their influence even if an endogenous ligand is bound to another site on the same target at the same time. By contrast, classical orthosteric drugs compete with endogenous ligands for the same site on a given target (see Fig. 1). This means that lower doses of allosteric modulators can have greater potency than orthosteric molecules with similar affinity. In other words, allosteric modulators could have fewer side effects compared to orthosteric molecules addressing the same target.
• Allosteric modulators can be devoid of activity in the absence of endogenous ligands. Because of this, allosteric modulators may offer a less disruptive way to influence the functioning of biological systems. In other words, because they do not perturb signaling on their own, they could preserve more of the natural biology compared to orthosteric approaches. Specifically, this could lead to greater safety and fewer side effects.
• Because they bind on a distinct site, Addex can create new chemical entities that re-address well validated GPCR targets for which there are marketed products – potentially with improved activity.
• For targets where it has been difficult to make selective orthosteric modulators in some cases highly selective allosteric modulators can be made. For example, Addex has made orally available small molecule allosteric modulators against some validated targets that the pharma industry has been unable to address using classical small molecule chemistry – like GLP-1 receptor and FSH receptor, for which only peptide, protein or hormonal therapies are available.
• Also because they bind on a distinct site, it is possible to combine allosteric modulators with orthosteric drugs. For example, a positive allosteric modulator, or PAM, could be used to potentiate an orthosteric agonist.
