The applications of binuclear metallohydrolases in medicine: Recent advances in the design and development of novel drug leads for purple acid phosphatases, metallo-β-lactamases and arginases

•Binuclear metallohydrolases are enzymes involved in various metabolic functions.•Several binuclear metallohydrolases are current targets for drug development.•Targeted disorders range from osteoporosis to erectile dysfunctions.•A major strategy to acquire antibiotic resistance involves enzymes from this group.•Potent inhibitors with nanomolar inhibition constants have recently been developed.

Binuclear metallohydrolases are a family of proteins that can be targeted for drug discovery. The common feature of these enzymes is the presence of two closely spaced metal ions (i.e. less than 4 Å apart) that capture a water molecule that is used as a nucleophile in highly specific hydrolytic reactions. In this mini-review we describe what is known about the biological and catalytic activity, three-dimensional structure and inhibition for three prominent drug targets in this family of enzymes, (i) purple acid phosphatases, (ii) metallo-β-lactamases and (iii) arginases. These enzymes are targets for the development of chemotherapeutics to treat a range of disorders including osteoporosis, cardiovascular disease and erectile dysfunctions, but also to stem the spread of antibiotic resistance, a major threat to global health care.

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