Exploiting computationally derived out-of-the-box protein conformations for drug design

Structural plasticity is an intrinsic property of proteins that allows each gene product to accomplish its tasks in a strictly regulated manner at a precise time and cellular location. Moreover, protein motions allow protein-ligand and protein-protein recognition. The knowledge of the conformational ensemble that a drug target populates may be crucial for the design of small molecules that can differently modulate its function. X-ray crystallography and NMR have endlessly provided snapshots of protein states. However, experimental structure determination is not always straightforward. Therefore, attempts have been made to depict protein conformational landscapes through molecular dynamics and enhanced sampling methods. Here, we review how accounting for protein dynamics through in silico generated out-of-the-box protein conformations has started to impact on drug discovery.