Over one-third of all proteins in the Protein Data Bank (PDB) and half of all classified enzymes contain metal ions. [2] These metalloenzymes are a part of crucial processes such as cellular respiration, nitrogen fixation, protein degradation and DNA replication. The most common metal ions found in enzymes are magnesium, zinc, sodium, calcium, iron, and manganese. [4] For instance, over 20% of all transferases, lyases, isomerases and ligases contain magnesium in the binding site, whereas zinc is found in at least 10% of all enzymes in each Enzyme Commission class. Since metalloenzymes are involved in so many important processes, their inhibition is sought for the treatment of different diseases and conditions, such as hepatitis C, cancer, hypertension, arthritis, and infections. For instance, the angiotensinconverting enzyme (ACE, EC 3.4.15.1) plays a pivotal role in regulating blood pressure and fluid balance. [8] ACE contains a Zn as cofactor, which is involved in catalyzing the hydrolysis of several peptides, such as the hydrolyzation of the hormone angiotensin I to the active vasoconstrictor angiotensin II. [8][9] ACE inhibitors, such as captopril and enalapril, are used in the treatment of medical conditions like hypertension, heart failure, diabetic nephropathy, and type 2 diabetes mellitus. The binding affinity of ACE inhibitors is partially driven by the interaction with the zinc ion in the active site, e. g. enalapril contains a carboxyl group that chelates the metal ion, while captopril contains a thiol group that interacts with the ion. A large database and analysis platform for metalloenzymes, the Metalloenzyme Data Bank and Analysis (MeDBA) platform has also been published. MeDBA contains information about metalloenzymes, their ligands and metalloenzyme-ligand interactions derived from the Protein Data Bank. Among others, the database includes 844 metal-chelating groups, called metal-binding pharmacophores (MBPs) in the MeDBA, derived from the ligands contained in it. To obtain these groups. the metal-chelating atoms were first detected using a rule-based approach. Then, the ligands were fragmented based on cleavage rules and the fragments which contained metal-chelating atoms were connected via their shortest path. Virtual or experimental screening of compound libraries is a common strategy to identify new enzyme inhibitors. Nowadays, a plenitude of screening libraries is available for drug discovery. While most available screening compounds have not been tailored to specific targets, some libraries have been specifically designed to target metalloenzymes or to contain metal chelators. Some chelator libraries, such as the ones from Life Chemicals and Otava, are comprised of drug-like compounds or fragments containing at least one chelating group. For instance, the compounds in the Life Chemicals chelator library were selected from their proprietary HTS Compound Collection, have passed a series of filters, including substructure, similarity and physicochemical properties, and did not contain toxic, bad or reactive groups. Some smaller, non-commercially available screening libraries have also been published. One of these libraries contains 96 compounds with two to four donor atoms for binding metal ions and suf ficient solubility for screening, however the details about how the metal binding groups were selected were not revealed. This library and its expansions were subsequently used for screening a range of metalloenzymes. Further, to enable fragment screening using 19F NMR, a small library containing 12 fluorinated compounds with different metal-chelating groups was assembled and evaluated against human carbonic anhydrase. Although metal-chelating groups can be extracted based on structural information contained in the PDB, to the best of our knowledge there has not yet been an extensive investigation of how well these groups are represented in screening libraries. Moreover, in recent years, large virtual, chemically accessible combinatorial spaces that can also be used in drug discovery have been encoded. For instance, Enamine's REAL space contains over 34 billion virtual products (11/2022), and WuXi LabNetwork's GalaXi space over 12 billion (03/2023). Analyzing these large spaces in terms of overlap and compound properties is not trivial, and little is known about their diversity. [25] As for the screening libraries, it is not known how well these large chemical spaces are suited to search for metalloenzymes inhibitors. SpaceMACS is a command line tool designed to enable efficient and precise maximum common substructure (MCS) searches within combinatorial chemical spaces which consequently also allows analyzing the representation of metal-chelating groups in chemical spaces. In this article, we report on the extraction of common metal-chelating groups from ligands interacting with some of the most common metal ions found in enzymes, magnesium (Mg 2+ ), manganese (Mn 2+ ) and zinc (Zn 2+ ). To assemble this list, we have searched the Protein Data Bank (PDB) for metalloproteins containing a ligand coordinated to the ions of interest. Subsequently, the chelating atoms of the identified ligands were determined and used to guide the extraction of metal-chelating groups. Further, we have analyzed how well the extracted metal-chelating groups are represented in various compound libraries and chemical spaces. Together, this work will support the discovery of inhibitors for enzymes containing Mg 2+ , Mn 2+ , or Zn 2+ in the active site.