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

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/982055
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