Accounting for water molecules in drug design

Importance of the field: 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 similar to 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. Areas covered in this review: 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. What the reader will gain: The reader will become aware of common practices and pitfalls in dealing with water molecules in structure-based drug design. Take home message: 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.