Medicinal chemistry of metal chelating fragments in metalloenzyme active sites: A perspective

Numerous metal-containing enzymes (metalloenzymes) have been considered as drug targets related to diseases such as cancers, diabetes, anemia, AIDS, malaria, bacterial infection, fibrosis, and neurodegenerative diseases. Inhibitors of the metalloenzymes have been developed independently, most of which are mimics of substrates of the corresponding enzymes. However, little attention has been paid to the interactions between inhibitors and active site metal ions. This review is focused on different metal binding fragments and their chelating properties in the metal-containing active binding pockets of metalloenzymes. We have enumerated over one hundred of inhibitors targeting various metalloenzymes and identified over ten kinds of fragments with different binding patterns. Furthermore, we have investigated the inhibitors that are undergoing clinical evaluation in order to help looking for more potential scaffolds bearing metal binding fragments. This review will provide deep insights for the rational design of novel inhibitors targeting the metal-containing binding sites of specific proteins.