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Identification of a chemical probe for NAADP by virtual screening

Identification of a chemical probe for NAADP by virtual screening
Identification of a chemical probe for NAADP by virtual screening
Research into the biological role of the Ca(2+)-releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with similar three-dimensional shape and electrostatic properties. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca(2+) increases in mouse pancreatic beta cells.
1552-4450
220-226
Naylor, Edmund
4d051d78-e1ce-42b0-bf32-bb4b22591f3b
Arredouani, Abdelilah
c3ad7c4e-760c-42e4-b349-84bbcc712be9
Vasudevan, Sridhar R.
bff5882f-aff0-42b9-adbe-a05512003ee2
Lewis, Alexander M.
653ad7ca-984c-4c2a-9e1b-0452f69c96f2
Parkesh, Raman
53bf51c3-a36f-49db-b073-5be15e526a8a
Mizote, Akiko
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Rosen, Daniel
c71e8db1-029c-403c-969d-2866f43e073e
Thomas, Justyn M.
f48ee69b-b969-4a4d-ac7f-e22ff729fcd7
Izumi, Minoru
09f507ed-6c5c-42ba-b127-13532414c78f
Ganesan, A.
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Galione, Anthony
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Churchill, Grant C.
1bfd3b90-5986-4019-978a-c3ee7720bb52
Naylor, Edmund
4d051d78-e1ce-42b0-bf32-bb4b22591f3b
Arredouani, Abdelilah
c3ad7c4e-760c-42e4-b349-84bbcc712be9
Vasudevan, Sridhar R.
bff5882f-aff0-42b9-adbe-a05512003ee2
Lewis, Alexander M.
653ad7ca-984c-4c2a-9e1b-0452f69c96f2
Parkesh, Raman
53bf51c3-a36f-49db-b073-5be15e526a8a
Mizote, Akiko
d858d2e2-e648-48f0-a2f8-e8a9c203b7c9
Rosen, Daniel
c71e8db1-029c-403c-969d-2866f43e073e
Thomas, Justyn M.
f48ee69b-b969-4a4d-ac7f-e22ff729fcd7
Izumi, Minoru
09f507ed-6c5c-42ba-b127-13532414c78f
Ganesan, A.
62aa5a87-9308-4383-8686-99726b6bcfb9
Galione, Anthony
8b37d2a7-fd5a-4666-ac6c-276a9a9ad328
Churchill, Grant C.
1bfd3b90-5986-4019-978a-c3ee7720bb52

Naylor, Edmund, Arredouani, Abdelilah, Vasudevan, Sridhar R., Lewis, Alexander M., Parkesh, Raman, Mizote, Akiko, Rosen, Daniel, Thomas, Justyn M., Izumi, Minoru, Ganesan, A., Galione, Anthony and Churchill, Grant C. (2009) Identification of a chemical probe for NAADP by virtual screening. Nature Chemical Biology, 5 (4), 220-226. (doi:10.1038/nchembio.150).

Record type: Article

Abstract

Research into the biological role of the Ca(2+)-releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with similar three-dimensional shape and electrostatic properties. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca(2+) increases in mouse pancreatic beta cells.

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Published date: 22 February 2009

Identifiers

Local EPrints ID: 160139
URI: http://eprints.soton.ac.uk/id/eprint/160139
ISSN: 1552-4450
PURE UUID: c8fb4a12-a90c-4cc2-b70e-809f886ed95b

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Date deposited: 12 Jul 2010 09:09
Last modified: 16 Jul 2019 23:54

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Contributors

Author: Edmund Naylor
Author: Abdelilah Arredouani
Author: Sridhar R. Vasudevan
Author: Alexander M. Lewis
Author: Raman Parkesh
Author: Akiko Mizote
Author: Daniel Rosen
Author: Justyn M. Thomas
Author: Minoru Izumi
Author: A. Ganesan
Author: Anthony Galione
Author: Grant C. Churchill

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