Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

Allostery is a fundamental and extensive mechanism of intramolecular signal transmission. Allosteric drugs possess several unique pharmacological advantages over traditional orthosteric drugs, including greater selectivity, better physicochemical properties, and lower off-target toxicity. However, owing to the complexity of allosteric regulation, experimental approaches for the development of allosteric modulators are traditionally serendipitous. Recently, the reversed allosteric communication theory has been proposed, providing a feasible tool for the unbiased detection of allosteric sites. Herein, we review the latest research on the reversed allosteric communication effect using the examples of sirtuin 6, epidermal growth factor receptor, 3-phosphoinositide-dependent protein kinase 1, and Related to A and C kinases (RAC) serine/threonine protein kinase B and recapitulate the methodologies of reversed allosteric communication strategy. The novel reversed allosteric communication strategy greatly expands the horizon of allosteric site identification and allosteric mechanism exploration and is expected to accelerate an end-to-end framework for drug discovery.