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Dolan, Jonathan P., Ahmadipour, Sanaz, Wahart, Alice J. C., Ní Cheallaigh, Aisling, Sari, Suat, Eurtivong, Chatchakorn, Lima, Marcelo A., Skidmore, Mark A., Volcho, Konstantin P., Reynisson, Jóhannes, Field, Robert A. 
ORCID: https://orcid.org/0000-0001-8574-0275 and Miller, Gavin J.
(2023)
Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors.
RSC Chemical Biology, 4 (11).
pp. 865-870.
ISSN 2633-0679
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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.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Information: UK Research and Innovation (UKRI, Future Leaders Fellowship, MR/T019522/1) and the Engineering and Physical Research Council (EP/P000762/1) are thanked for project grant funding to GJM and the Scientific and Technological Research Council of Turkey (TÜBITAK, 2219 Program, 1059B192200422) for project funding to SS. |
| Uncontrolled Keywords: | chemistry (miscellaneous),biochemistry,molecular biology,biochemistry, genetics and molecular biology (miscellaneous) ,/dk/atira/pure/subjectarea/asjc/1600/1601 |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 03 Sep 2024 09:36 |
| Last Modified: | 25 Sep 2024 18:04 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/96459 |
| DOI: | 10.1039/d3cb00126a |
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