Detailed thermodynamic analysis of fragment binding revealed that unlike drug-like
compounds, fragments bind with significant enthalpic preference. This observation
is in line with the size dependency of binding enthalpy contributions and is also
supported by a large body of experimental data from direct binding thermodynamic measurements.
The enthalpy-driven binding of fragments represents a thermodynamic rationale for
fragment-based drug discovery programs and suggests guidelines for fragment-based
optimization programs.
