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

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.