Which cryptic sites are feasible drug targets?

Cryptic sites can expand the space of druggable proteins, but the potential usefulness of such sites needs to be investigated before any major effort. Given that the binding pockets are not formed, the druggability of such sites is not well understood. The analysis of proteins and their ligands shows that cryptic sites that are formed primarily by the motion of side chains moving out of the pocket to enable ligand binding generally do not bind drug-sized molecules with sufficient potency. By contrast, sites that are formed by loop or hinge motion are potentially valuable drug targets. Arguments are provided to explain the underlying causes in terms of classical enzyme inhibition theory and the kinetics of side chain motion and ligand binding.