Projects per year
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.
Original language | English |
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Pages (from-to) | 309-315 |
Number of pages | 7 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 11 |
Issue number | 3 |
Early online date | 18 Oct 2019 |
DOIs | |
Publication status | Published - 12 Mar 2020 |
Keywords
- 5-phosphatase
- HPLC
- Inositol phosphate
- SHIP2
- TD-DFT
- fluorescence
- ligand
Profiles
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Charles Brearley
- School of Biological Sciences - Professor of Biochemistry
- Molecular Microbiology - Member
- Plant Sciences - Member
Person: Research Group Member, Academic, Teaching & Research
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Vasily Oganesyan
- School of Chemistry, Pharmacy and Pharmacology - Reader in Computational Chemistry
- Centre for Molecular and Structural Biochemistry - Member
- Centre for Photonics and Quantum Science - Member
- Chemistry of Life Processes - Member
- Chemistry of Light and Energy - Member
Person: Research Group Member, Research Centre Member, Academic, Teaching & Research
Projects
- 1 Finished