Thermodynamic Data Remain a Hot Tip for Decoding Binding Affinity and Water Impact on Protein–Ligand Complex Formation to Assist Lead Optimization

Optimization of screening hits from lead-finding campaigns into promising lead candidates can be supported by factorizing thermodynamic binding profiles into enthalpic and entropic contributions. Given that data are recorded for large multicomponent systems, typically affected by substantial enthalpy/entropy compensation, it is exceedingly challenging to directly assign enthalpy and entropy to rational design concepts. Correcting recorded data for superimposed protonation steps and analyzing structural and dynamic properties is essential. Subsequently, thermodynamic signatures can be assigned to related ligand pairs. However, profile-determining contributions can vary from case-to-case, even steps prior to protein binding can be determinant. Pocket solvation, prior to or during ligand binding, can have substantial influence on binding profiles, leading to more enthalpy or entropy-driven profiles. Since a range from dry to well-solvated pockets is observed, different thermodynamic signatures can be recorded. The quality of newly formed surface-solvation shells generated after ligand binding can significantly impact ligand affinity.