Calculating the Gibbs energies of binding of ligand-receptor systems with a thermochemical accuracy of ± 1 kcal mol-1 is a challenge to computational approaches. After exploration of the conformational space of the host, ligand and their resulting complexes upon coordination by semi-empirical GFN2 MD and meta-MD simulations, the systematic refinement through a multi-level improvement of binding modes in terms of electronic energies and solvation is able to give Gibbs energies of binding of drug molecules to CB[8] and β-CD macrocyclic receptors with such an accuracy. The accurate treatment of a small number of structures outperforms system-specific force-matching and alchemical transfer model approaches without an extensive sampling and integration.