Accounting for Solvent in Structure-Based Drug Design

Water plays a crucial role in the mediation of protein–ligand interactions, as underscored by the fact that most X-ray crystal structures (of sufficient resolution) of protein–ligand complexes possess water molecules at the protein–ligand interface. In this chapter, the accuracy and reliability of ordered waters observed in crystal structures is discussed. Additionally, the thermodynamic aspects of the inclusion of water in ligand binding to proteins is described, with the goal of providing practical guidelines for dealing with ordered water molecules during structure-guided lead optimization.