Protein flexibility is an important component of structure-based drug discovery

Receptor-based drug discovery can increase the novelty of a hit list over ligand-based models that are dependent on known inhibitors. It is important to explore new conformational and chemical space, but it is difficult to predict the plasticity of the binding site. Receptor-based methods are usually based on crystal structures of ligand-protein complexes, and hit lists can be restricted to the size and shape of the receptor model. Many improvements that accommodate protein flexibility in computer-aided drug design are being developed. These methods are reviewed with the focus being techniques that move beyond the rotation of side chains. The use of multiple protein structures is emerging as the best choice for including more realistic changes in protein conformation, but the optimal way to using these structures is still unclear.