Skip to main content
eScholarship
Open Access Publications from the University of California

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

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

Published Web Location

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01868
No data is associated with this publication.
Abstract

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 (FBDD) 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.

Item not freely available? Link broken?
Report a problem accessing this item