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

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• 作者：Mattia Mori ; Ylenia Cau ; Giulia Vignaroli ; Ilaria Laurenzana ; Antonella Caivano ; Daniela Vullo ; Claudiu T. Supuran ; Maurizio Botta
• 刊名：ACS Chemical Biology
• 出版年：2015
• 出版时间：September 18, 2015
• 年：2015
• 卷：10
• 期：9
• 页码：1964-1969
• 全文大小：340K
• ISSN：1554-8937

文摘

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鈥?0, a false-positive hit highlighted in a cell-based screen for 14鈥?鈥? modulators. Although GV2鈥?0 does not bind to 14鈥?鈥? proteins, it showed remarkable antiproliferative effects in CML cells, thus raising interest toward the identification of its primary target. Six potential targets of GV2鈥?0 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鈥?0 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.