Allosteric binding sites on cell-surface receptors: novel targets for drug discovery
@article{Christopoulos2002AllostericBS,
title={Allosteric binding sites on cell-surface receptors: novel targets for drug discovery},
author={Arthur Christopoulos},
journal={Nature Reviews Drug Discovery},
year={2002},
volume={1},
pages={198-210}
}Cell-surface receptors are the targets for more than 60% of current drugs. Traditionally, optimizing the interaction of lead molecules with the binding site for the endogenous agonist (orthosteric site) has been viewed as the best means of achieving selectivity of action. However, recent developments have highlighted the fact that drugs can interact with binding sites on the receptor molecule that are distinct from the orthosteric site, known as allosteric sites. Allosteric modulators could…
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References
SHOWING 1-10 OF 148 REFERENCES
Allosteric binding sites on muscarinic receptors
- Chemistry
- 1997
The classical (acetylcholine) binding sites of all five subtypes of muscarinic receptors are known to be subject to allosteric regulation by a variety of small molecules. The hallmarks of such…
G Protein-Coupled Receptor Allosterism and Complexing
- Biology, MedicinePharmacological Reviews
- 2002
It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.
Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site
- Biology, MedicineProceedings of the National Academy of Sciences of the United States of America
- 2001
Two chemical series of compounds acting as selective positive allosteric modulators of native and recombinant metabotropic glutamate 1 (mGlu1) receptors were identified, markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy.
Modeling the functional effects of allosteric modulators at pharmacological receptors: an extension of the two-state model of receptor activation.
- Chemistry, MedicineMolecular pharmacology
- 2000
A mathematical model of allosteric interactions at pharmacological receptors has been investigated and used to provide a potential mechanistic explanation for the functional effects of the A(1) adenosine receptor allosterIC enhancer PD 81,723 and a recently reported allosterics modulator of type 1 metabotropic glutamate receptors.
Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods.
- Chemistry, MedicineMolecular pharmacology
- 1988
The theoretical basis for using radioligand binding and pharmacological techniques to estimate the dissociation constants of drugs which interact allosterically with receptors is described and the effect of changes in affinity and intrinsic efficacy of the agonist-receptor complex is predicted.
Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins.
- Chemistry, MedicineProceedings of the National Academy of Sciences of the United States of America
- 1989
It is shown that for a member of this family of receptors (delta opioid receptors in membranes of NG108-15 neuroblastoma-glioma cells), two types of competitive antagonists can be distinguished and one has no intrinsic activity and the second can inhibit GTPase and thus exhibits negative intrinsic activity.
Structural and functional aspects of G protein-coupled receptor oligomerization.
- MedicineBiochemistry and cell biology = Biochimie et biologie cellulaire
- 1998
Evidence is reviewed that receptor oligomerization and in particular dimerization may play an important role in the molecular events leading to GPCR activation, and biochemical and functional evidence supporting this notion is reviewed.
Inverse, protean, and ligand‐selective agonism: matters of receptor conformation
- Biology, MedicineFASEB journal : official publication of the Federation of American Societies for Experimental Biology
- 2001
Evidence for the existence of the various types of agonism and the potential therapeutic utility of differ¬ent agonist types is reviewed.
A Pharmacologic Analysis of Drug-Receptor Interaction
- Chemistry
- 1987
Drug receptor/theory seven transmembrane receptor behaviour human recombinant receptor systems stimulus-response mechanisms drug response mechanisms diffusion and drug concentration in receptor…
Probing of the location of the allosteric site on m1 muscarinic receptors by site-directed mutagenesis.
- Chemistry, MedicineMolecular pharmacology
- 1995
In an attempt to locate the allosteric site on muscarinic receptors to which gallamine binds, 21 residues in the putative external loops and loop/transmembrane helix interfaces have been mutated to…