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.