2. Academic Validation
  3. Hit Recycling: Discovery of a Potent Carbonic Anhydrase Inhibitor by in Silico Target Fishing

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

  • ACS Chem Biol. 2015 Sep 18;10(9):1964-9. doi: 10.1021/acschembio.5b00337.
Mattia Mori 1 2,  Ylenia Cau 1,  Giulia Vignaroli 1,  Ilaria Laurenzana 3,  Antonella Caivano 3,  Daniela Vullo 4,  Claudiu T Supuran 4 5,  Maurizio Botta 1 6
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via Aldo Moro 2, I-53100 Siena, Italy.
  • 2 Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia , viale Regina Elena 291, I-00161 Roma, Italy.
  • 3 IRCCS-Centro di Riferimento Oncologico Basilicata (CROB) , Laboratory of Preclinical and Translational Research, Via Padre Pio 1, Rionero in Vulture 85028 Potenza, Italy.
  • 4 Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy.
  • 5 Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze , Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.
  • 6 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.
PMID: 26121309 DOI: 10.1021/acschembio.5b00337
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-123365
    Carbonic Anhydrase 2 Inhibitor