Complexes from PDBbind were prepared following the same procedure of our previous work . For retrospective VS, dominant protonation and tautomerization state was computed from the small molecule SMILES using Openeye 's QUACPAC . Resulting SMILES strings were then converted into low-energy 3D conformations (mol2 format) using Openeye 's OMEGA tool . The target proteins were prepared as follows: redundant protein chains, along with non-essential ions, waters, and heteroatoms, were removed. The resulting protein structures were prepared using the Molecular Operating Environment (MOE) QuickPrep tool , by automatically adding missing loops in the structure and assigning the proper conformation to the residues with alternate orientation. Subsequently, protonation states were generated and optimized using the Protonate 3D tool from MOE (at pH 7.4). Finally, the structures were energy-minimized using the AMBER10:EHT forcefield implemented in MOE , and saved in pdb format.