Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

TY - JOUR

T1 - Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

AU - Schwartz, Thue W

AU - Holst, Birgitte

N1 - Keywords: Allosteric Regulation; Binding Sites; Humans; Ligands; Models, Biological; Pharmaceutical Preparations; Protein Binding; Receptors, GABA; gamma-Aminobutyric Acid

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1016/j.tips.2007.06.008

DO - 10.1016/j.tips.2007.06.008

M3 - Journal article

C2 - 17629958

SN - 0165-6147

VL - 28

SP - 366

EP - 373

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

IS - 8

ER -