Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?
Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites of several ordinary allosteric enhancers and ago-allosteric modulators seem to overlap with those of the endogenous agonists. Different molecular scenarios are proposed to explain this discrepancy from classical allosteric models. In one scenario, the ago-allosteric modulator can interchange between different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug.
Schwartz
Thue W
TW
Laboratory for Molecular Pharmacology, Institute of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. schwartz@molpharm.dk
Holst
Birgitte
B
D000494:Allosteric Regulation; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D018079:Receptors, GABA / Q000737:chemistry / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D004364:Pharmaceutical Preparations; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid