Regioisomeric family of novel fluorescent substrates for SHIP2

White, Gaye, Prior, Christopher, Mills, Stephen J., Baker, Kendall, Whitfield, Hayley, Riley, Andrew M, Oganesyan, Vasily S. ORCID:, Potter, Barry V. L. and Brearley, Charles A. ORCID: (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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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
Additional Information: Copyright © 2019 American Chemical Society.
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
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
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Depositing User: LivePure Connector
Date Deposited: 28 Oct 2019 15:23
Last Modified: 09 Mar 2024 01:17
DOI: 10.1021/acsmedchemlett.9b00368


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