Cryptic binding site Cryptic binding sites are hidden or transient regions that are not evident when the protein is inactive or not bound ( ). However, these cryptic sites either arise or become accessible when a ligand hooks to the protein or when its form changes (Figure ). These cryptic sites depend on particular conditions or the presence of specialist ligands for their visibility, so they are often invisible using typical structural research techniques such as X-ray crystallography or NMR spectroscopy ( ). Since they offer fresh drug discovery and development opportunities, especially for targets that have been difficult to control using conventional orthosteric or allosteric sites, identifying and understanding hidden binding sites is vital. Thus, various compotation strategies have been designed to investigate cryptic binding sites and understand their mechanisms.