Abstract
Research into the biological role of the Ca2+-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 Ca2+ increases in mouse pancreatic beta cells.
| Original language | English |
|---|---|
| Pages (from-to) | 220-226 |
| Number of pages | 7 |
| Journal | Nature Chemical Biology |
| Volume | 5 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2 2009 |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
Identification of a chemical probe for NAADP by virtual screening. / Naylor, Edmund; 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.
In: Nature Chemical Biology, Vol. 5, No. 4, 02.04.2009, p. 220-226.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of a chemical probe for NAADP by virtual screening
AU - Naylor, Edmund
AU - Arredouani, Abdelilah
AU - Vasudevan, Sridhar R.
AU - Lewis, Alexander M.
AU - Parkesh, Raman
AU - Mizote, Akiko
AU - Rosen, Daniel
AU - Thomas, Justyn M.
AU - Izumi, Minoru
AU - Ganesan, A.
AU - Galione, Antony
AU - Churchill, Grant C.
PY - 2009/4/2
Y1 - 2009/4/2
N2 - Research into the biological role of the Ca2+-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 Ca2+ increases in mouse pancreatic beta cells.
AB - Research into the biological role of the Ca2+-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 Ca2+ increases in mouse pancreatic beta cells.
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U2 - 10.1038/nchembio.150
DO - 10.1038/nchembio.150
M3 - Article
C2 - 19234453
AN - SCOPUS:62649161780
VL - 5
SP - 220
EP - 226
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 4
ER -