Evidence map›Paper›PMID 38742480›Full record

ArticleChemMedChem2024

Fluoromethylketone-Fragment Conjugates Designed as Covalent Modifiers of EcDsbA are Atypical Substrates.

Bradley C Doak, Rebecca L Whitehouse, Kieran Rimmer, Martin Williams, Begoña Heras, Sofia Caria, Olga Ilyichova, Mansha Vazirani, Biswaranjan Mohanty, Jason B Harper and 2 more

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In one paragraph

Article in ChemMedChem, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Bradley C DoakMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Rebecca L WhitehouseMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Kieran RimmerMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Martin WilliamsMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Begoña HerasDepartment of Biochemistry and Genetics, La Trobe, La Trobe University, Kingsbury Drive, Bundoora, Vic, 3083, Australia.
Sofia CariaMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Olga IlyichovaMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Mansha VaziraniMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Biswaranjan MohantyMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Jason B HarperSchool of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia.
Martin J ScanlonMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.ORCID https://orcid.org/0000-0002-9230-7506
Jamie S SimpsonMedicinal Chemistry, ARC Centre for Fragment-Based Design, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.

Funding

APAARC IC180100021Monash UniversityNHMRC 1009785NHMRC 455860PPA
6 · The paper itself

Abstract

Disulfide bond protein A (DsbA) is an oxidoreductase enzyme that catalyzes the formation of disulfide bonds in Gram-negative bacteria. In Escherichia coli, DsbA (EcDsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment-based screen was conducted against EcDsbA and herein we describe the development of a series of compounds based on a phenylthiophene hit identified from the screen. A novel thiol reactive and "clickable" ethynylfluoromethylketone was designed for reaction with azide-functionalized fragments to enable rapid and versatile attachment to a range of fragments. The resulting fluoromethylketone conjugates showed selectivity for reaction with the active site thiol of EcDsbA, however unexpectedly, turnover of the covalent adduct was observed. A mechanism for this turnover was investigated and proposed which may have wider ramifications for covalent reactions with dithiol-disulfide oxidoreducatases.

Indexed as

Escherichia coliEscherichia coli ProteinsKetonesAnti-Bacterial AgentsEnzyme InhibitorsMolecular StructureProtein Disulfide-IsomerasesStructure-Activity RelationshipSubstrate SpecificityAnti-Bacterial AgentsdsbA protein, E coliEnzyme InhibitorsEscherichia coli ProteinsKetonesProtein Disulfide-IsomerasesEnzymesInhibitorsNMR spectroscopyProtein Structure

Identifiers

PMID38742480
PMCPMC13494810

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.