Chemical accuracy for ligand-receptor binding Gibbs energies through multi-level SQM/QM calculations

Calculating the Gibbs energies of binding of ligand-receptor systems with a thermochemical accuracy of ± 1 kcal/mol is challenge to computational approaches. A semi-empirical quantum chemical exploration of the conformational space of host, ligand and complexes followed by a multi-level refinement of poses 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 receptor with such an accuracy. The accurate treatment of a small number of poses outperforms system-specific force-matching and alchemical transfer model approaches without an extensive sampling and intergration.