There are a plethora of structure-based methods to calculate ΔGbind, broadly classified as end-point (e.g., Molecular Mechanics with Poisson-Boltzmann and Surface Area Solvation (MM/PBSA)), path-sampling (e.g., meta-dynamics or adaptive biasing force), and alchemical methods (e.g., Thermodynamic Integration (TI) or Free Energy Perturbation (FEP)). These do not require pre-existing data, but end-point methods are rather inaccurate, while the rest are computationally expensive and offer variable performance.