A study that explains how the carbohydrate sialyl Lewisx binds to the protein E-selectin in blood capillaries could lead to improved drugs for inflammatory conditions. Selectin proteins on surfaces of endothelial cells in blood capillaries play a key role in inflammation-related diseases such as rheumatoid arthritis and psoriasis. Selectin blockers that might alleviate such conditions are being sought, but finding druglike agents that bind tightly to selectins, as the natural ligand sialyl Lewisx does, has proven difficult. To better understand the driving force of the sialyl Lewisx/E-selectin interaction, Beat Ernst and coworkers at the University of Basel studied its detailed thermodynamics (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201202555). They found that an array of directed hydrogen bonds on sialyl Lewisx enables it to selectively bind E-selectin. Sialyl Lewisx acts as what the team calls a “preorganized water oligomer” on a scaffold, unexpectedly making the binding interaction largely entropy-driven. The entropy of the interaction is increased, favoring complex formation, the researchers say, because ligand binding displaces a large number of water molecules from the binding interface to bulk water. These details could help refine efforts to design new selectin-blocking agents.