It is now well known that proteins represent major targets for drug discovery. Drug discovery is
based on the concept that drugs bind with the proteins and inhibit their functions, which
otherwise become the cause of some diseases. Earlier, it was assumed that proteins had fixed
conformation and used to be in a single well-defined state, able to accommodate only one
optimal complementary ligand. Such a system corresponded to the “lock-and-key” model of the
binding. However, the most important point to consider is that introducing a ligand into the
system also changes the environment. It too may affect the most populated state of the protein;
such a case would correspond to an “induced-fit” model. It is thought that a single protein
structure is only useful to identify ligands for that particular narrow state of the subensemble.
However, in order to obtain new leads and properly predict activity of existing inhibitors,
multiple structures are the best option. Thus, rather than viewing a protein in a fixed state, it was
argued that a protein molecule may exist in a full complement of conformations—most in the
native state, some in the induced-fit state, and some in other states. Thus, if the ligand binds
preferentially to the induced-fit state with sufficiently favorable free energy, the average
structure of the protein will change. Thus, the simplistic “lock and key” model has been
superseded by more realistic views of molecular recognition that take into account the intrinsic
dynamics of biological macromolecules, which is now called as protein flexibility, and therefore
people have started investigating relationship between protein flexibility and binding free energy
and presenting some useful hints for understanding when, and to what extent, flexibility should
be considered. Protein flexibility is now supposed to be fundamental in the mode of drugreceptor
intercations. Various docking methods accounting for protein flexibility have been
proposed, tackling problems of ever-increasing dimensionality, as it allows now the increased affinity to be achieved between a drug and its target. Molecular docking is widely used to predict
the structure of protein-ligand complexes, and protein flexibility stands out as one of the most
important and challenging issues for binding and discovering the potent drugs. However, we are
not close to the end of the problem, but just at the beginning. Therefore, this hot topic issue is
aimed to present such articles on protein flexibility, invited from potential authors, which may
show further directions to researchers to come closer to the problem. As we come closer to
problem, we will gain more insight into the drug discovery