Allosteric solution to the problems of undruggable targets, drug toxicity, and emerging resistance

Abstract

Though allostery is a well-established research field, its importance for biomedical applications, spanning from the allosteric effects of mutations in diagnostics to the design of innovative allosteric drugs, is yet to be fully appreciated. The potential of allostery in resolving issues of current drug design and in targeting proteins considered difficult or undruggable is the main topic of this review. In particular, we discuss how the non-conservatism of allosteric sites enables selective targeting of individual members in conserved families, thereby minimizing off-target toxicity. The multiplicity of allosteric sites in any structure allows alleviation of challenges posed by emerging drug resistance driven by allosteric and orthosteric mutations. The modulatory action of allosteric drugs provides, at the same time, an important therapeutic advantage in gradual activation/inhibition of enzymatic function and signaling in receptors. We also discuss here an approach for rational design of allosteric drugs, illustrating its process and output in obtaining effectors with the above-mentioned advantages and characteristics. Reviewing recent advances in the development of allosteric effectors, we show that allostery is undoubtedly becoming an integral part of the drug discovery paradigm. We, therefore, anticipate that the pharmaceutical industry will be prompted to systematically incorporate allostery as an important complement to existing drug design strategies in the near future.