binding enthalpy

Binding enthalpy is the heat-content part of the energy story when a drug latches onto its target. Roughly, it tracks how good the actual bonds and contacts are: a favorable (negative) enthalpy means the new hydrogen bonds, salt bridges and van der Waals contacts the drug makes are stronger and better-matched than the ones it and the pocket gave up to water.

Enthalpy is one of the two ingredients of binding free energy, alongside entropy. It is often measured directly by isothermal titration calorimetry (ITC), which detects the tiny heat released or absorbed as ligand and protein combine. A strongly enthalpy-driven binder usually owns a set of well-formed, precisely positioned polar interactions.

Many chemists prize enthalpy-driven binders because tight, specific polar contacts are thought to be harder to achieve and to give cleaner selectivity than simply burying greasy surface. But this is a tendency, not a rule: enthalpy and entropy trade off through enthalpy–entropy compensation, so an enthalpy gain from a new hydrogen bond is frequently clawed back by an entropy loss, and only the combined free energy decides affinity.