Discovery of hidden allosteric sites as novel targets for allosteric drug design

Hidden allosteric sites, as a novel type of allosteric site, are invisible in ligand-unbound (apo) crystal structures, but can emerge in ligand-bound (holo) crystal structures when a specific ligand binds to, and stabilizes, a unique conformation favored by the ligand. However, the identification of these sites is a significant challenge. Several computational and experimental approaches have been developed to identify such sites in proteins. Here, we outline these approaches, with a focus on examples of the successful use of such techniques. The discovery of hidden allosteric sites offers a new avenue for facilitating drug design by greatly expanding the repertoire of available drug targets, contributing to the search for allosteric drugs for the treatment of human diseases.