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

## TL;DR

Thermodynamic data help understand how proteins and ligands bind, aiding drug development by revealing how water affects binding affinity.

## Contribution

The paper introduces a method to analyze thermodynamic profiles to decode the impact of water and binding steps on ligand affinity.

## Key findings

- Pocket solvation before or during ligand binding influences thermodynamic profiles.
- Surface-solvation shells after ligand binding significantly impact ligand affinity.
- Enthalpy and entropy contributions vary and require correction for accurate design insights.

## Abstract

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.