Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening.

ABSTRACT: 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 nonselective 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 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throu

SUBMITTER: Resnick E 

PROVIDER: S-EPMC6556873 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature