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Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors †

Dolan, Jonathan; Ahmadipour, Sanaz; Wahart, Alice; Ni Cheallaigh, Aisling; Sari, Suat; Eurtivong,, Chatchakorn; Lima, Marcelo; Skidmore, Mark; Volcho, Konstantin; Reynisson, Jóhannes; Field, Robert; Miller, Gavin

Authors

Sanaz Ahmadipour

Alice Wahart

Aisling Ni Cheallaigh

Suat Sari

Chatchakorn Eurtivong,

Konstantin Volcho

Robert Field



Abstract

Upon undergoing mucoid conversion within the lungs of cystic fibrosis patients, the pathogenic bacterium Pseudomonas aeruginosa synthesises copious quantities of the virulence factor and exopolysaccharide alginate. The enzyme guanosine diphosphate mannose dehydrogenase (GMD) catalyses the rate-limiting step and irreversible formation of the alginate sugar nucleotide building block, guanosine diphosphate mannuronic acid. Since there is no corresponding enzyme in humans, strategies that could prevent its mechanism of action could open a pathway for new and selective inhibitors to disrupt bacterial alginate production. Using virtual screening, a library of 1447 compounds within the Known Drug Space parameters were evaluated against the GMD active site using the Glide, FRED and GOLD algorithms. Compound hit evaluation with recombinant GMD refined the panel of 40 potential hits to 6 compounds which reduced NADH production in a time-dependent manner; of which, an usnic acid derivative demonstrated inhibition six-fold stronger than a previously established sugar nucleotide inhibitor, with an IC50 value of 17 μM. Further analysis by covalent docking and mass spectrometry confirm a single site of GMD alkylation.

Journal Article Type Article
Acceptance Date Aug 26, 2023
Online Publication Date Aug 29, 2023
Publication Date Aug 29, 2023
Deposit Date Sep 6, 2023
Publicly Available Date Sep 11, 2023
Journal RSC Chemical Biology
Print ISSN 2633-0679
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 4
Issue 11
Pages 865-870
DOI https://doi.org/10.1039/D3CB00126A
Keywords cystic fibrosis; bacteria; screening
Publisher URL https://pubs.rsc.org/en/content/articlelanding/2023/cb/d3cb00126a

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