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PMID: 19234453 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Identification of a chemical probe for NAADP by virtual screening.

Nature chemical biology ·Vol. 5 ·No. 4 ·2009-04-00 ·Pages 220-6

Naylor E, Arredouani A, Vasudevan SR, Lewis AM, Parkesh R, Mizote A, Rosen D, Thomas JM, Izumi M, Ganesan A, Galione A, Churchill GC

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.

MeSH Terms
Animals Carbolines/chemistry,pharmacology Cyclic ADP-Ribose/pharmacology Inositol 1,4,5-Trisphosphate/pharmacology Insulin-Secreting Cells/drug effects Mice Models, Molecular Molecular Structure NADP/analogs & derivatives,chemistry,metabolism Ovum/chemistry Piperazines/chemistry,pharmacology Sea Urchins Small Molecule Libraries
Chemicals
1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid Carbolines Piperazines Small Molecule Libraries Cyclic ADP-Ribose NADP NAADP Inositol 1,4,5-Trisphosphate
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Naylor Edmund
Department of Pharmacology, University of Oxford, Oxford, UK.
Arredouani Abdelilah
Vasudevan Sridhar R
Lewis Alexander M
Parkesh Raman
Mizote Akiko
Rosen Daniel
Thomas Justyn M
Izumi Minoru
Ganesan A
Galione Antony
Churchill Grant C
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Article Info
Journal
Nature chemical biology
Abbr.
Nat Chem Biol
ISSN
1552-4469
DOI
10.1038/nchembio.150
Published
2009-04-00
Epub
2009-00-22
Pages
220-6
Language
English
Region
United States
NLM ID
101231976
PMCID
PMC2659327
Subset
IM
Grants
Biotechnology and Biological Sciences Research Council · BB/D012694/1 · United Kingdom
Biotechnology and Biological Sciences Research Council · BB/G008523/1 · United Kingdom
Databases
PubChem-Substance
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External Links
PubMed source DOI: 10.1038/nchembio.150 PMC Full Text View journal details
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