Accounting for water molecules in drug design

Water molecules often appear around ligands in protein crystal structures. Reliable prediction of the effects of water on ligand binding remains a challenge. Solvation effects are crucial for lead optimization where a 100-fold difference in binding affinity is significant but correspond to only ∼3 kcal/mol in binding free energy. Well-known examples, such as nonpeptidic urea inhibitors of HIV protease, prove that careful examination of water molecules and their energetics can contribute significantly to a successful drug design campaign.

In this review, we examine methods to account for the effect of water in ligand binding at two stages of drug discovery: lead identification via docking calculations and lead optimization. We provide a survey of the models and techniques available to account for water in drug design.

The reader will become aware of common practices and pitfalls in dealing with water molecules in structure-based drug design.

Although solvation effects are not fully understood, some pragmatic recommendations at the end of the article provide guidance for modelers in this area as well as new practitioners.