In silico target fishing is an emerging tool in drug discovery, which is mostly used for primary target or off-target prediction and drug repositioning. In this work, we developed an in silico target fishing protocol to identify the primary target of GV2-20, a false-positive hit highlighted in a cell-based screen for 14-3-3 modulators. Although GV2-20 does not bind to 14-3-3 proteins, it showed remarkable antiproliferative effects in CML cells, thus raising interest toward the identification of its primary target. Six potential targets of GV2-20 were prioritized in silico and tested in vitro. Our results show that the molecule is a potent inhibitor of carbonic anhydrase 2 (CA2), thus confirming the predictive capability of our protocol. Most notably, GV2-20 experienced a remarkable selectivity for CA2, CA7, CA9, and CA12, and its scaffold was never explored before as a chemotype for CA inhibition, thus becoming an interesting lead candidate for further development.

Mori, M., Cau, Y., Vignaroli, G., Laurenzana, I., Caivano, A., Vullo, D., et al. (2015). Hit Recycling: Discovery of a Potent Carbonic Anhydrase Inhibitor by in Silico Target Fishing. ACS CHEMICAL BIOLOGY, 10(9), 1964-1969 [10.1021/acschembio.5b00337].

Hit Recycling: Discovery of a Potent Carbonic Anhydrase Inhibitor by in Silico Target Fishing

MORI, MATTIA;CAU, YLENIA;VIGNAROLI, GIULIA;LAURENZANA, ILARIA;BOTTA, MAURIZIO
2015-01-01

Abstract

In silico target fishing is an emerging tool in drug discovery, which is mostly used for primary target or off-target prediction and drug repositioning. In this work, we developed an in silico target fishing protocol to identify the primary target of GV2-20, a false-positive hit highlighted in a cell-based screen for 14-3-3 modulators. Although GV2-20 does not bind to 14-3-3 proteins, it showed remarkable antiproliferative effects in CML cells, thus raising interest toward the identification of its primary target. Six potential targets of GV2-20 were prioritized in silico and tested in vitro. Our results show that the molecule is a potent inhibitor of carbonic anhydrase 2 (CA2), thus confirming the predictive capability of our protocol. Most notably, GV2-20 experienced a remarkable selectivity for CA2, CA7, CA9, and CA12, and its scaffold was never explored before as a chemotype for CA inhibition, thus becoming an interesting lead candidate for further development.
2015
Mori, M., Cau, Y., Vignaroli, G., Laurenzana, I., Caivano, A., Vullo, D., et al. (2015). Hit Recycling: Discovery of a Potent Carbonic Anhydrase Inhibitor by in Silico Target Fishing. ACS CHEMICAL BIOLOGY, 10(9), 1964-1969 [10.1021/acschembio.5b00337].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/982055
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