The Role of Water in Protein–Ligand Binding: Decisive Factor, Annoying Feature, or Indispensable Control Element: In Any Case, a Major Challenge

Evolution began in water; it's not surprising that water had a profound influence on protein–ligand complex formation. However, water's contribution to binding is low, perhaps up to ±5 kJ/mol for displacement or recruitment. When affinity is factorized into enthalpy and entropy, a large scatter of both is observed, especially when both mutually compensate. Since this also applies to water, its impact can easily be overlooked and go unnoticed, especially when only affinity data are available. Nevertheless, water can enhance ligand affinity when a well‐designed solvation shell assembles around the formed protein–ligand complex. Examples are discussed of pockets exhibiting varying water density in uncomplexed proteins, or transient pockets that only open with ligand binding. Are these pockets solvated before the ligand enters, or can the ligand penetrate without allowing water molecules to temporarily fill the pocket? Rules are needed to help medicinal chemists select the best optimization strategy while considering water's impact.