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

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 Zn 2+-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.

Application of Fragment-Based Drug Discovery to Versatile Targets

“…MS and X-ray Sijbesma et al, 2019 The RNA-dependent RNA polymerase X-ray Riccio et al, 2019 Apical membrane antigen 1 PRE, NMR Akter et al, 2019 Glyoxalase 1 Computational approach Perez et al, 2019 Focal Adhesion Kinase SPR and NMR Alvarado et al, 2019 E. coli DsbA NMR/X-ray Duncan et al, 2019 PDEδ-RAS (PPI) STD, CMPG-NMR Chen et al, 2019 *This table lists some studies using FBDD. Only a few studies published in 2019 were list for elucidating the application of FBDD to multiple targets.…”

The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening

“…It is estimated that 10% of human proteins utilise zinc to support structure, function, or both [ 7 ], therefore, it is not surprising that fragment screening campaigns with zinc metalloproteins have been pursued. For example, Cohen and colleagues have used fragment libraries with a composition bias toward known metal binding pharmacophores for screening with a range of zinc metalloproteins [ 8 , 9 , 10 ]. Our team has a long-standing interest in discovery of novel inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), a family of zinc metalloenzymes that catalyse the reversible hydration of CO 2 to give HCO 3 − and H + [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

“…Redknown zinc binding groups of carboxylic acid (1-3) and primary sulfonamide (4). Blue-Novel zinc binding groupstetrazole (5-6), 1,2,4-triazole (7) and 3-unsubstituted oxazolidinedione (8).…”

Genetic and Pharmacological Manipulations of Glyoxalase 1 Mediate Ethanol Withdrawal Seizure Susceptibility in Mice

“…Genetic and pharmacological manipulations of the GLO1 system, as well as direct administration of MG, have been associated with changes in anxiety- and depression-like behaviors, ethanol consumption, and the seizure threshold. Specifically, decreased anxiety-like behavior [ 23 , 24 ], decreased depression-like behavior [ 25 , 26 ], decreased ethanol consumption [ 27 , 28 ], and decreased susceptibility to pilocarpine- and picrotoxin-induced seizures [ 29 ] have all been seen following GLO1 inhibitor treatment. Some of these effects are also produced by the genetic knockdown of Glo1 or direct MG administration.…”