Introduction: Hidden allosteric sites are not visible in apo-crystal structures, but they may be visible in holo-structures when a certain ligand binds and maintains the ligand intended conformation. Several computational and experimental techniques have been used to investigate these hidden sites but identifying them remains a challenge.
Areas covered: This review provides a summary of the many theoretical approaches for predicting hidden allosteric sites in disease-related proteins. Furthermore, promising cases have been thoroughly examined to reveal the hidden allosteric site and its modulator.
Expert opinion: In the recent past, with the development in scientific techniques and bioinformatics tools, the number of drug targets for complex human diseases has significantly increased but unfortunately most of these targets are undruggable due to several reasons. Alternative strategies such as finding cryptic (hidden) allosteric sites are an attractive approach for exploitation of the discovery of new targets. These hidden sites are difficult to recognize compared to allosteric sites, mainly due to a lack of visibility in the crystal structure. In our opinion, after many years of development, MD simulations are finally becoming successful for obtaining a detailed molecular description of drug-target interaction.
Keywords: Markov state models; apo/holo-crystal; enhanced sampling; hidden allosteric site; mixed-solvent.