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Identification of New Fyn Kinase Inhibitors Using a FLAP-Based Approach

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    Identification of New Fyn Kinase Inhibitors Using a FLAP-Based Approach
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    † Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
    ‡ Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, CRO, Aviano, 33081 Pordenone, Italy
    § Dipartimento Farmaco Chimico Tecnologico, Università di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy
    ∥ Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy
    *Phone: +39 0502219595. E-mail: [email protected]
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    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2013, 53, 10, 2538–2547
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ci4002553
    Published September 3, 2013
    Copyright © 2013 American Chemical Society
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    Abstract

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    The abnormal activity of Fyn tyrosine kinase has been shown to be related to various human cancers. Furthermore, its involvement in signaling pathways that lead to severe pathologies, such as Alzheimer’s and Parkinson’s diseases, has also been demonstrated, thus making Fyn an attractive target for the discovery of potential novel therapeutics for brain pathologies and tumors. In this study we evaluated the reliability of various screening approaches based on the FLAP software. By the application of the best procedure, the virtual screening workflow was used to filter the Gold and Platinum database from Asinex to identify new Fyn inhibitors. Enzymatic assays revealed that among the eight top-scoring compounds five proved to efficiently inhibit Fyn activity with IC50 values in the micromolar range. These results demonstrate the validity of the methodologies we followed. Furthermore, the five active compounds herein described may be considered as interesting leads for the development of new and more efficient Fyn inhibitors.

    Copyright © 2013 American Chemical Society

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    Supporting Information

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    Known active Fyn inhibitors, H-bond analysis of the staurosporine–Fyn complex, and representative compounds belonging to the new four clusters identified by means of the VS workflow refinement (Table S1, S2 and S3); superimposition between Fyn and PKA kinase, rescoring results of the filtered enriched database after docking calculations, superimposition between the X-ray structure of Fyn kinase and the region used for the MD simulations, analysis of the MD simulation of staurosporine complexed with Fyn kinase; and superimposition between Fyn and EGFR binding site. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2013, 53, 10, 2538–2547
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ci4002553
    Published September 3, 2013
    Copyright © 2013 American Chemical Society
    Request reuse permissions

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