First, all missing loops were modeled using Modeller-9.24, and then the proteins were prepared for docking calculations using the Schrödinger Suite 2019 Protein Preparation workflow [Schrödinger Suite 2019 Protein Preparation Wizard]. The generation of alternative structural variants (stereoisomers, alternative ionization, and protonation states) was done with LigPrep v53013. An Epik State Penalty threshold of 1.5 was imposed to filter out lowfrequency structural variants. Docking was conducted with Glide v86013 (mmshare version 49013), using the SP scoring function but with special settings to increase the number of generated poses, and thus the number of protein-ligand or protein-decoy (henceforth stated as "protein-ligand" for shortness) complexes for subsequent MM energy minimization and PM6-D3H4X/COSMO scoring. The full set of parameters, which is provided in the Supporting Info (Table ), includes also clustering criteria to remove redundant poses. Only poses with Glide SP score within a window of 1 kcal mol were retained for PM6-D3H4X/COSMO scoring, as in our tests scoring all generated poses led to the deterioration of VS performance and a dramatic increase of the computational cost.