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

Eur J Med Chem. 2014 Apr 9:76:132-44. doi: 10.1016/j.ejmech.2014.02.008. Epub 2014 Feb 8.

Abstract

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.

Keywords: Antibiotic; Drug development; Metalloenzymes; Osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acid Phosphatase / antagonists & inhibitors*
  • Acid Phosphatase / chemistry
  • Arginase / antagonists & inhibitors*
  • Arginase / chemistry
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycoproteins / antagonists & inhibitors*
  • Glycoproteins / chemistry
  • Hydrolases / drug effects*
  • Metalloproteins / antagonists & inhibitors*
  • Metalloproteins / chemistry
  • Models, Molecular
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / chemistry

Substances

  • Enzyme Inhibitors
  • Glycoproteins
  • Metalloproteins
  • beta-Lactamase Inhibitors
  • Hydrolases
  • purple acid phosphatase
  • Acid Phosphatase
  • beta-Lactamases
  • Arginase