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Open Access Publications from the University of California

Metal-Binding Pharmacophore Library Yields the Discovery of a Glyoxalase 1 Inhibitor.

  • Author(s): Perez, Christian;
  • Barkley-Levenson, Amanda M;
  • Dick, Benjamin L;
  • Glatt, Peter F;
  • Martinez, Yadira;
  • Siegel, Dionicio;
  • Momper, Jeremiah D;
  • Palmer, Abraham A;
  • Cohen, Seth M
  • et al.

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Anxiety and depression are common, highly comorbid psychiatric diseases that account for a large proportion of worldwide medical disability. Glyoxalase 1 (GLO1) has been identified as a possible target for the treatment of anxiety and depression. GLO1 is a Zn2+-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester. To develop active inhibitors of GLO1, fragment-based drug discovery was used to identify fragments that could serve as core scaffolds for lead development. After screening a focused library of metal-binding pharmacophores, 8-(methylsulfonylamino)quinoline (8-MSQ) was identified as a hit. Through computational modeling and synthetic elaboration, a potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore. A lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice. These findings provide the basis for GLO1 inhibitors to treat depression and related psychiatric illnesses.

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