displaced water

Before any drug arrives, a binding pocket is not empty — it is full of water. When the ligand moves in, it kicks some of those water molecules out and sends them back into the surrounding solution. Whether kicking out a particular water helps or hurts binding turns out to be one of the most important and underappreciated factors in affinity.

The key is how comfortable each water was in the pocket. A water trapped in a greasy, nonpolar spot, unable to make its usual hydrogen bonds, is unhappy and high in energy; displacing it releases a lot of favorable free energy and is a great way to gain potency. But a water sitting in a polar pocket where it forms several good hydrogen bonds is content and well-bound; evicting that water costs energy and can weaken binding unless the ligand fully repays those lost hydrogen bonds.

This is why a single methyl or small group placed to displace one 'unhappy' water can sometimes give an outsized jump in potency, while a change that strips out a 'happy' bridging water can unexpectedly kill activity. Modern structure-based design uses simulations and tools to predict which pocket waters are worth displacing and which are better left in place or matched.