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White, Gaye, Prior, Christopher, Mills, Stephen J., Baker, Kendall, Whitfield, Hayley, Riley, Andrew M., Oganesyan, Vasily S. 
ORCID: https://orcid.org/0000-0002-8738-1146, Potter, Barry V. L. and Brearley, Charles A. ORCID: https://orcid.org/0000-0001-6179-9109
(2020)
Regioisomeric family of novel fluorescent substrates for SHIP2.
ACS Medicinal Chemistry Letters, 11 (3).
pp. 309-315.
ISSN 1948-5875
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Abstract
SHIP2 (SH2-domain containing inositol 5-phosphatase type 2) is a canonical 5-phosphatase which, through its catalytic action on PtdInsP3, regulates the PI3K/Akt pathway and metabolic action of insulin. It is a drug target but there is limited evidence of inhibition of SHIP2 by small molecules in the literature. With the goal to investigate inhibition, we report a homologous family of synthetic, chromophoric benzene phosphate substrates of SHIP2 that display the headgroup regiochemical hallmarks of the physiological inositide substrates that have proved difficult to crystallize with 5-phosphatases. Using time-dependent density functional theory (TD-DFT), we explore the intrinsic fluorescence of these novel substrates and show how fluorescence can be used to assay enzyme activity. The TD-DFT approach promises to inform rational design of enhanced active site probes for the broadest family of inositide-binding / metabolizing proteins, whilst maintaining the regiochemical properties of bona fide inositide substrates.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | 5-phosphatase,hplc,inositol phosphate,ship2,td-dft,fluorescence,ligand,biochemistry,drug discovery,organic chemistry ,/dk/atira/pure/subjectarea/asjc/1300/1303 |
| Faculty \ School: | Faculty of Science > School of Biological Sciences Faculty of Science > School of Chemistry (former - to 2024) |
| UEA Research Groups: | Faculty of Science > Research Groups > Plant Sciences Faculty of Science > Research Groups > Molecular Microbiology Faculty of Science > Research Groups > Chemistry of Light and Energy Faculty of Science > Research Groups > Chemistry of Life Processes Faculty of Science > Research Centres > Centre for Molecular and Structural Biochemistry Faculty of Science > Research Groups > Centre for Photonics and Quantum Science |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 28 Oct 2019 15:23 |
| Last Modified: | 17 Oct 2024 00:20 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/72808 |
| DOI: | 10.1021/acsmedchemlett.9b00368 |
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