Given the critical role of accurately describing intermolecular interactions in many docking and scoring methods, particularly physics-and interaction-based approaches, we applied a detailed structure preparation protocol using the Protein Preparation Wizard from Maestro (Protein Preparation Wizard; Epik, Schrödinger, LLC, New York, NY, 2023; Prime, Schrödinger, LLC, New York, NY, 2023). The assignment of protonation states to protein atoms and the optimization of the hydrogen-bond network, including flips of Asn, Gln, and His, were performed using PROPKA and considered the presence of the ligand and cofactors based on the experimental pH in the original PDB structure . When unavailable, pH 7 was assumed. Metal ions were considered cofactors, and the water molecules were removed from the complexes. The protonation and tautomeric states of the ligand were calculated using Epik. For docking experiments, only the best-predicted state was retained (Epik, Schrödinger, LLC, New York, NY, 2022) .