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., Potter, Barry V. L. and Brearley, Charles A. (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
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
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Depositing User: LivePure Connector
Date Deposited: 28 Oct 2019 15:23
Last Modified: 21 Jul 2021 01:25
DOI: 10.1021/acsmedchemlett.9b00368

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