Metal Chelation in Enzyme Active Sites for Drug Discovery

Expert-driven In Silico Drug Discovery Solutions
12 May 2021
Svitlana Kondovych
Senior Researcher

Metal ions in biomolecules play essential roles in cellular functionality, enabling mechanisms inaccessible to purely organic compounds. Metals promote various biochemical reactions, support transport and regulatory processes, and stabilize enzyme structures. Overall, metalloproteins comprise up to 40% of the proteome [1]; this remarkable diversity opens up numerous possibilities to exploit metal chelation, or metal-ligand interactions, in drug design projects [2-5].

One major research direction focuses on metal-containing drugs [6] that deliver metal ions into cells where needed. Existing metallodrugs mainly serve as anticancer agents due to their high cytotoxicity. Platinum-based drugs, e.g., cisplatin and its derivatives, are widely used in chemotherapy; however, novel treatment strategies employ some less toxic metals, such as gold or ruthenium [7].

Another principal approach engages metal chelation processes for the development of metal-targeting drugs. The usual scenario is as follows: small-molecule organic compounds chelate metal ions of the targeted biomolecule and, thus, modulate its activity. Main chelation-based pharmacological strategies ([8], Fig.1) include altering metal biodistribution, enhancing or passivating metal reactivity, and inhibiting metalloenzymes – proteins, whose metal ions catalyze organic chemical reactions.

Main approaches that use principles of metal chelation

Fig.1. Main approaches that use principles of metal chelation

Metalloenzyme inhibitors form one of the most promising medication classes used to treat various pathologies, including cancer, viral and bacterial infections, neurodegenerative and other diseases [9]. They act via binding to the metal centers of disease-related enzyme catalytic sites and hindering their functionality (Fig.1). Among the most widespread metals present in metalloenzymes are zinc, copper, magnesium, iron, and manganese; accordingly, metalloenzyme inhibitors contain different functional groups intended to chelate a particular metal ion.

A broad spectrum of zinc-based enzymes comprises, among others, carbonic anhydrases (maintain pH of the blood), histone deacetylases (regulate acetylation), and a large family of matrix metalloproteinases involved in the degradation of extracellular matrix proteins. These enzymes serve as promising targets for the treatment of various diseases, most often in anticancer research [9,10].


The excessive amount of copper brings about cytotoxic cellular damages and may result in oncological and neurodegenerative disorders. Thereby, copper-binding ligands are promising candidates for the corresponding therapies [11].


Iron enzymes catalyze oxidative reactions and thus take part in a vast variety of vital processes; iron-chelating ligands are employed to treat cancer, neurological disorders, infectious diseases [3,9].


Magnesium enzymes regulate the metabolism of nucleic acids. The inhibition of the activity of Mg2+-dependent targets assists anti-cancer, anti-HIV/AIDS, anti-inflammatory therapies [3,9].


Manganese-dependent enzymes support the antioxidation processes, synthesis of fatty acids, neurotransmitter levels regulation, and many other vital functions [12]. Excessively accumulated manganese may trigger neurodegenerative diseases, such as Parkinson’s. Mn2+-chelating compounds (Fig.2) contribute to the treatment of cancer, viral infections, and brain disorders [9].


Spatial structure of a catalytic subunit complex of protein phosphatase type 5 from cantharidin,  with LC analog and Mn+2 ion molecules

Fig.2. Spatial structure of a catalytic subunit complex of protein phosphatase type 5 from cantharidin,
with LC analog and Mn+2 ion molecules

The development of metal-coordinating drugs builds upon the interplay of experimental and computational techniques, with the escalating role of the latter. Atomic-level simulations ofmetal-ligand interactions [2-4] advance and corroborate the discovery of metallodrugs and metalloenzyme inhibitors, promoting faster and more accurate outcomes. Besides, in silico prediction approaches, such as similarity search and molecular docking, generate plentiful libraries of small organic molecules that can be applied as potential chelating ligands.

The Life Chemicals HTS Compound Collection features the following range of libraries related to metal chelation: 

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  2. Riccardi, L., Genna, V. & De Vivo, M. (2018). Metal–ligand interactions in drug design. Nat Rev Chem 2, 100–112. DOI: 10.1038/s41570-018-0018-6
  3. Palermo, G., Spinello, A., Saha, A., & Magistrato, A. (2020). Frontiers of metal-coordinating drug design, Expert Opinion on Drug Discovery, 1-15. DOI: 10.1080/17460441.2021.1851188
  4. Spinello, A., Borisek, J., Pavlin, M., Janos, P. and Magistrato, A. (2021), Computing metal‐binding proteins for therapeutic benefit. ChemMedChem. Accepted Author Manuscript. DOI: 10.1002/cmdc.202100109
  5. Sales, T.A., Prandi, I.G., Castro, A.A., et al. (2019). Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments. Int J Mol Sci. 20(8):1829. DOI: 10.3390/ijms20081829
  6. Anthony, E. J., Bolitho, E. M., Bridgewater, et al. (2020). Metallodrugs are unique: opportunities and challenges of discovery and development. Chem. Sci.,,11, 12888-12917. DOI: 10.1039/D0SC04082G
  7. Murray, B. S., & Dyson, P. J. (2020). Recent progress in the development of organometallics for the treatment of cancer. Current Opinion in Chemical Biology, 56, 28–34. DOI:10.1016/j.cbpa.2019.11.001
  8. Franz, K. J. (2013). Clawing back: broadening the notion of metal chelators in medicine. Current Opinion in Chemical Biology, 17(2), 143–149. DOI:10.1016/j.cbpa.2012.12.021
  9. Chen, A. Y., Adamek, R. N., Dick, B. L., Credille, C. V., Morrison, C. N., & Cohen, S. M. (2019). Targeting Metalloenzymes for Therapeutic Intervention. Chem. Rev., 119, 2, 1323–1455. DOI:10.1021/acs.chemrev.8b00201
  10. Ye, R., Tan, C., Chen, B., Li, R., and Mao, Z. (2020). Zinc-Containing Metalloenzymes: Inhibition by Metal-Based Anticancer Agents. Front. Chem. 8:402. DOI: 10.3389/fchem.2020.00402
  11. Wang, J., Luo, C., Shan, C., You, Q., et al. (2015). Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. Nature Chemistry, 7(12), 968–979. DOI:10.1038/nchem.2381
  12. Soares, M. V., Quines, C. B., & Ávila, D. S. (2020). Manganese. Essential and Toxic Trace Elements and Vitamins in Human Health, 141–152. DOI:10.1016/b978-0-12-805378-2.00010-3
12 May 2021, 15:11 Svitlana Kondovych Computational Chemistry

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