Tuesday, May 7, 2019

Rapid covalent-probe discovery by electrophile-fragment screening [@london_lab]

Efrat ResnickAnthony BradleyJinrui GanAlice DouangamathTobias KrojerRitika SethiPaul P. GeurinkAnthony AimonGabriel AmitaiDom BelliniJames BennettMichael FairheadOleg FedorovRonen Gabizonjin ganJingxu GuoAlexander PlotnikovNava ReznikGian Filippo RudaLaura Díaz-SáezVerena M. StraubTamas SzommerSrikannathasan VelupillaiDaniel ZaidmanYanling ZhangAlun R. CokerChristopher G DowsonHaim BarrChu WangKilian V. M. HuberPaul E BrennanHuib OvaaFrank von Delft, and Nir London

Journal of the American Chemical Society 2019
DOI: 10.1021/jacs.9b02822

Covalent probes can display unmatched potency, selectivity and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered non-selective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against ten cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. By contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]

 Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...