We used an in-house version of the Cuby4 51 software to automate our fragmentation, optimization, and energy calculation protocols. The PM6 with the D3H4X corrections was employed along with the COSMO implicit solvent , hereafter quoted as "PM6/COSMO" for shortness. The SQM scoring setup used here is based on the earlier work done in the Hobza group but it does not include further developments made there after 2018. For each protein-ligand complex, an SQM geometry optimization is conducted including by default only the compound in the SQM part, and then the optimized complex geometry underwent SQM scoring. We also assessed the effect of the inclusion of protein residues in the SQM part during geometry optimization. Due to their high computational cost, such calculations were restricted to our smallest dataset, the Acetylcholinesterase (ACHE), and were conducted in two schemes: (i) only protein residues within 4 Å of the COM of the ligand were included, or (ii) only within 6 Å. The total score of binding between the protein and compound structures is given by the following equation: