Novel allosteric sites

Novel allosteric sites are binding regions on a protein that are topographically distinct from the orthosteric site where natural substrates or ligands bind (Lu et al., 2014). These sites are of significant interest in drug discovery because they can regulate protein function through conformational transitions, often providing greater subtype selectivity and a different safety profile than orthosteric ligands (Nussinov & Tsai, 2013). By binding to these sites, allosteric modulators can either enhance or inhibit the activity of the target protein in a manner that is often saturable, potentially reducing the risk of overdose-related toxicity (Wenthur et al., 2014). However, 'Novel allosteric sites' is a general structural descriptor rather than a specific biological target, receptor, or enzyme. It encompasses a wide range of potential pockets across various protein classes, including G protein-coupled receptors, kinases, and ion channels. These sites are frequently targeted to address previously 'undruggable' proteins or to overcome drug resistance caused by mutations in the orthosteric pocket. Identifying such sites often requires advanced computational methods or structural biology techniques like X-ray crystallography and cryo-electron microscopy. Because the term does not refer to a single molecular entity, it cannot be associated with a specific set of interacting drugs or clinical biomarkers.

Other names

Allosteric binding sitesNon-orthosteric sitesExositesCryptic pocketsSecondary binding sites

Modulation of protein activity (activation, inhibition, or neutral) through induced conformational changes upon binding to a site distinct from the orthosteric pocket (Lu et al., 2014).