Importance of Allostery in Pharmacology

Allostery refers to the binding of a metabolite at a site other than the chemically active site of a protein. The existence of allosteric sites on receptor molecules has expanded potential drug mechanisms.

The first class of drugs to demonstrate allostery were the benzodiazepines, which are allosteric ligands for a neurotransmitter γ-aminobutyric acid (GABA) receptor.

Since then, many other allosteric ligands have been developed as drugs for a range of targets, including ion channels, kinases, caspases, G protein-coupled receptors, and phospholipases.

Allosteric and Orthosteric Ligands

A ligand that binds the chemically active site of a protein is known as an orthosteric ligand. For example, the orthosteric ligand for kinases is adenosine triphosphate. For GPCRs and ion channels, the orthosteric ligands are small neurotransmitters like glutamate and GABA or large peptides.

Synthetic orthosteric ligands compete for occupancy of the binding site, and can have different pharmacological roles like inhibitor, agonist, antagonist, or inverse antagonist. However, drugs that act as orthosteric ligands can suffer from a lack of efficacy.

In GPCRs and ion channels, allosteric ligands can have a number of different pharmacological effects, such as positive allosteric modulation (PAMs) which potentiate agonist-mediated receptor response and negative allosteric modulators (NAMs) which decrease activity without competing with the native ligand.

Some allosteric agonists bind both the orthosteric and the allosteric sites. These are called bitopic ligands.

Allosteric Binding Sites

Allosteric binding sites are distinct from the orthosteric binding site, and they allow for many different ligand-receptor interactions beyond those controlled by the orthosteric site. They have greater selectivity than the orthosteric site as they bind under less evolutionary pressure. An allosteric modulator can also preserve the activity of the endogenous ligand.

Allosteric Ligands for Kinases

Kinases are enzymes that phosphorylate other proteins. This phosphorylation often serves the purpose of cellular signaling. To carry out this activity, kinase binds to ATP via an ATP binding pocket which is highly conserved.

Orthosteric kinase inhibitors that compete with ATP are called Type I inhibitors. There are three additional classes of allosteric ligands for kinases: Type II inhibitors bind at both the ATP site and an adjacent allosteric binding pocket; Type III inhibitors bind exclusively to allosteric binding pockets near the ATP binding site; Type II and Type III inhibitors inactivate kinases by locking it in an inactive conformation; Type IV inhibitors bind to allosteric sites far removed from the ATP binding site.

Types of Allosteric Ligands

Ago-allosteric ligands

Some allosteric ligands have complex relationships with orthosteric ligands. An ago-allosteric ligand mediates a receptor response in the absence of an orthosteric ligand, while also potentiating the receptor in the presence of an orthosteric ligand.

Allosteric agonists

Allosteric agonists are allosteric ligands that activate the receptor in the absence of an endogenous ligand.

Bitopic ligands

Bitopic ligands have two binding groups: one binds orthosterically and the other binds allosterically. Thus, it is able to target both orthosteric and allosteric binding sites on a single receptor.

Reviewed by P Surat, PhD


  1. Analytical pharmacology and allosterism: the importance of quantifying drug parameters in drug discovery (
  2. Drugs for allosteric sites on receptors (
  3. An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology  (
  4. The design of covalent allosteric drugs, (

Further Reading

Last Updated: Jun 29, 2018


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