The individual terms describe the gas-phase interaction energy (∆E int ), the change of solvation free energy upon complex formation (∆∆G solv (L)), the change of conformational 'free' energy of the protein (∆G conf w (P ) SQM/M M ), and ligand (∆G conf w (L) SQM/M M ) in the aqueous environment and the change of entropy upon ligand binding (T ∆S int ). The terms ∆G conf w (P ) SQM/M M and ∆G conf w (L) SQM/M M are also known as strain energies and are defined as the difference between the free energy of conformations of the bound and the unbound state. The protein unbound state is the same for all complexes of the same receptor and hence this term cancels out during score comparison. In the case of ∆G conf w (L) SQM/M M , the compound unbound state is the minimum energy conformation obtained by conformer generation as described above. In our standard VS protocol, we perform just a subtle MM energy minimization and subsequently an SQM optimization of the compound only. Therefore, the protein structure remains almost the same in all protein-ligand complexes of the same receptor and thus the protein Entropy term (T ∆S int ) can be safely neglected as it almost cancels out during binding score comparison. However, this term is no longer negligible when protein residues are also included in the SQM part during geometry optimization. In that case, no further estimation of the protein binding Entropy was pursued. A grand total of 1,495,500 protein-ligand structures that passed successfully through all the above-described steps were scored on the PM6/COSMO level totaling 1.2 million core hours.