Unless otherwise mentioned, all data preparation and processing pipelines were built in-house using Python 3.10.0 and the Biopython 49 library. Since most PDB files contain multiple chains of proteins or macromolecules, each PDB file assess in this study was dissected for chain specific assessment, cleaned off from all ligands and/or double checked for errors with the associated covalent residue in the PDB. Any PDB chain alone with a covalent ligand sitting on a non-cavity site (absence of non-covalent interaction), missing the covalent residue in questions, or imperceptibly cryptic was omitted from analysis. Where applicable and unless otherwise mentioned, the positive covalent residue for each PDB was extracted and its respective negative was assigned by taking the most distant matching residue (matching false positive) within the chain.