title: Hit Recycling: Discovery of a Potent Carbonic Anhydrase Inhibitor by in Silico Target Fishing.
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.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via Aldo Moro 2, I-53100 Siena, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia , viale Regina Elena 291, I-00161 Roma, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Cau
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vignaroli
authors.affiliation: IRCCS-Centro di Riferimento Oncologico Basilicata (CROB) , Laboratory of Preclinical and Translational Research, Via Padre Pio 1, Rionero in Vulture 85028 Potenza, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Laurenzana
authors.affiliation: IRCCS-Centro di Riferimento Oncologico Basilicata (CROB) , Laboratory of Preclinical and Translational Research, Via Padre Pio 1, Rionero in Vulture 85028 Potenza, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Caivano
authors.affiliation: Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy.|Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via Aldo Moro 2, I-53100 Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University , BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D058492:Drug Repositioning; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D062105:Molecular Docking Simulation
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases