Journal
EXPERT OPINION ON DRUG DISCOVERY
Volume 6, Issue 1, Pages 65-74Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/17460441.2011.534452
Keywords
computation; docking; drug design; hit identification; lead identification; lead optimization; water
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Funding
- US Department of Energy, Office of Science, Offices of Advanced Scientific Computing Research, and Biological & Environmental Research through the U.C. Merced Center for Computational Biology [DE-FG02-04ER25625]
- US Department of Energy by Lawrence Livermore National Laboratory [AC52-07NA27344]
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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.
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