2.4. Induced-fit ligand docking

Top scoring ligands in each class of drug were extracted and re-submitted to the induced-fit docking (IFD) module implemented in the Maestro v12 algorithm, which employs a mixed molecular docking and dynamic protocol. Briefly, the standard IFD protocol was applied to the selected (centroid) amino acid side chains (19–29, 38–54, 85, 114–119, 126, 136–147, 161–175, 181, 185–193) in an implicit solvent model using the OPLS_2005 force field. H-bond and metal ion constraints were applied to both the initial and re-docking stages. Ring conformational sampling with a 2.5 kcal/mol energy barrier, as well as a non-planar conformation penalty on amide bonds was applied to the IFD protocol. The scaling for both receptor and ligand was set at 0.5 with a maximum of 20 allowable poses per ligand. Residues within 5 Å of the docked ligand were further refined using Prime Refinement algorithm implemented in Maestro v12. Prime energy was used to rank the refined protein-ligand complexes. The receptor structures within 30 kcal/mol of the minimum energy structure were submitted for a final round of Glide docking and scoring. Each ligand was re-docked into every single refined low-energy receptor structure in the subsequent second docking step using the default Glide XP settings.