Proteins are not static objects. To carry out their functions in the cells and participate in biochemical interaction
networks, proteins have to explore different conformational substates, which favor the adaptation to different partners and
ultimately allow them to respond to changes in the environment. In this paper we discuss the implications of including the
atomistic description of protein dynamics and flexibility in the context of drug discovery and design. The underlying idea
is that a better understanding of the atomistic details of molecular recognition phenomena and conformational cross-talk
between a ligand and a receptor can in fact translate in unexplored opportunities for the discovery of new drug like molecules.
We will illustrate and discuss dynamics-based pharmacophores, the discovery of cryptic binding sites, the characterization
and exploitation of allosteric regulation mechanisms and the definition of potential protein-protein interaction
sites as potential sources of new bases for the rational design of small molecules endowed with specific biological functions.
Overall, the inclusion of protein flexibility in the drug discovery process is starting to attract attention not only in
the academic but also in the industrial community. This is supported by experimental tests that prove the actual feasibility
of considering the explicit dynamics of drug-protein interactions at all relevant levels of resolution and the use of multiple
receptor conformations in drug discovery, as affordable complements (if not an alternative) to classical High Throughput
Screening (HTS) efforts based on static structures.
Keywords: Allostery, Disease, Drug design, Protein dynamics, Protein function, Protein structure.
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