The conversion into 3D structure, adjustment of the protonation states and energy minimization were subsequently prepared in the software Molecular Operation Environment ). The hydroxamic acid structure was used in its deprotonated form. The available protein structure of hHDAC1 was downloaded from the Protein Data Bank (PDB ID: 5ICN) and MTA1 was removed from HDAC1:MTA1 complex. For PfHDAC1 a previously reported homology model of PfHDAC1 was employed. The respective proteins were prepared in MOE by adding hydrogen atoms and building missing loops. Water molecules, ligands and ions (except the catalytic zinc ion) were removed from the structures. The docking procedures were conducted with GOLD in combination with the HERMES visualizer (Cambridge Crystallographic Data Centre, version 2022.3.0). Both enantiomers were docked within radius of 15 Å around the catalytic zinc ion. All poses were optimized within 50 GA runs and scored with ChemPLP. The early termination option of the docking runs was not allowed. The search efficiency was set to 200%. The docking was carried out with a substructure-based distance constraint to limit the distance between the zinc ion and the atoms of the zinc binding group. For this purpose, the hydroxamate substructure (CONO) of the co-crystallized ligand in hHDAC1 (PDB ID: 5ICN) was used as a template, which was also placed to the active site of the homology model of PfHDAC1 by structural alignment. A minimum and a maximum separation of 1.5 Å to 3.5 Å and a spring constant of 5 between the zinc ion and the complexing atoms O2 and O1 of the hydroxamate were defined. The side chains of the respective amino acids Asp97 (PfHDAC1) and Asp99 (hHDAC1) were specified as flexible upon docking. The allowed rotamers are defined from a rotamer library. The docking solutions were selected by visual inspection according to a reasonable zinc binding and orientation of the cap group. The respective docking results in Figure were visualized using MOE. Compound 9d was docked to hHDAC1 (PDB ID: 5ICN) using the same parameters as for the docking of 18b.