Prior to energy minimization, the geometry of docking poses was optimized on the PM7/ COSMO level of theory and partial charges were computed. As in our tests, PM7 produced better geometries, but PM6 exhibited higher AUC-ROC and enrichment rates, this is the only step in which we do not use PM6 Hamiltonian. Using the optimized docking pose geometries, the GAFF2 force field parameters of each compound, specifically the equilibrium bond lengths and angles, were corrected on the fly. AM1-BCC partial charges were computed from the PM7/COSMO pre-optimized geometries without any further geometry optimization. We chose PM7 for geometry optimization instead of PM6-D3H4X because with the former we obtained better structures, while the latter yielded better P-L interaction free energies. To accelerate the MM simulations whilst emulating explicit solvent conditions around the binding site, the following protocol was employed: The AmberFF14SB protein force field was used to neutralize each protein-ligand system using Cl -and/or N a + counterions, and explicit TIP3P water within a sphere of radius 20 Å from the center of mass (COM) of the compound. Non-bonded interactions beyond a cutoff distance of 18 Å were ignored.