Global hinge sites of proteins as target sites for drug binding

Hinge sites of proteins play a key role in mediating conformational mechanics. Among them, those involved in the most collective modes of motion, also called global hinges, are of particular interest, as they support cooperative rearrangements that are often functional. Yet, the utility of targeting global hinges for modulating function remains to be established. We present here a systematic study of a series of proteins resolved in drug-bound forms to examine the probabilistic occurrence of spatial overlaps between hinge sites and drug-binding pockets. Our analysis reveals a high propensity of drug binding to hinge sites compared to random. Notably, one-third of currently approved drugs are colocalized with hinge sites. These mechanosensitive sites are predictable by simple models such as the Gaussian Network Model. Their targeting thus emerges as a viable strategy for developing a new class of drugs that would exploit and modulate the target proteins' intrinsic dynamics, and potentially alleviate drug-resistance when used in combination with orthosteric or allosteric drugs.