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

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posted on 2019-01-10, 00:00 authored by Christian Perez, Amanda M. Barkley-Levenson, Benjamin L. Dick, Peter F. Glatt, Yadira Martinez, Dionicio Siegel, Jeremiah D. Momper, Abraham A. Palmer, Seth M. Cohen
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.