Allosteric Proteins and Drug Discovery

Abstract The existence of allosteric phenomena in the control of proteins allows for exquisite control of many of the cell's normal processes. Allosteric interactions involve the binding of an “allosteric” ligand to a site other than the functional (active) site of the protein, with a concomitant alteration in activity. Two major theoretical models have been presented to explain allosteric interactions, that of Monod, Wyman, and Changeux and that of Koshland, Nemethy, Filmer, Dalziel, and Engel. Although there are essential differences between the two models, both require that allosteric ligands interact with one or more forms of the protein to trigger a modulating effect. In only a few cases, much structural detail is known about more than one conformational state of any given allosteric protein, or how the binding of small‐molecule effectors to an allosteric site triggers protein modulation. Our current understanding of how conformational signals may be transmitted between proteins is assessed, particularly in the light of recent discussion of intrinsically disordered regions of proteins. Methods for identifying potential ligands that may elicit allosteric effects is also discussed. In this chapter, the essential features of allosteric enzymes and allosteric models are examined in a context that leads to consideration of how drugs may be designed such that they either mimic or block normal allosteric effects. Several existing “allosteric” drugs, and a number of potential targets for the rationale design of future allosteric drugs, are discussed.