Unraveling structural mechanisms of allosteric drug action

•Allosteric drug discovery should be rooted in the principles of allostery.•Allosteric drugs can comprise anchor and pushing or pulling driver atoms.•Pushing/pulling driver atoms can determine the agonist/antagonist outcome.•We map a strategy for distinguishing between agonist and antagonist in drug development.

Orthosteric drugs block the active site to obstruct function; allosteric drugs modify the population of the active state, to modulate function. Available data lead us to propose that allosteric drugs can constitute anchors and drivers. The anchor docks into an allosteric pocket. The conformation with which it interacts is unchanged during the transition between the inactive and active states. The anchor provides the foundation that allows the driver to exert a ‘pull’ and/or ‘push’ action that shifts the receptor population from the inactive to the active state. The presence or absence of driver atom in an allosteric drug can exert opposite agonism. We map a strategy for driver identification and expect the allosteric trigger concept to transform agonist/antagonist drug discovery.