Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors
Issued Date
2023-01-01
Resource Type
eISSN
26330679
Scopus ID
2-s2.0-85172277871
Journal Title
RSC Chemical Biology
Rights Holder(s)
SCOPUS
Bibliographic Citation
RSC Chemical Biology (2023)
Suggested Citation
Dolan J.P., Ahmadipour S., Wahart A.J.C., Cheallaigh A.N., Sari S., Eurtivong C., Lima M.A., Skidmore M.A., Volcho K.P., Reynisson J., Field R.A., Miller G.J. Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors. RSC Chemical Biology (2023). doi:10.1039/d3cb00126a Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/90286
Title
Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors
Other Contributor(s)
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.