Identification of new Fyn kinase inhibitors using a FLAP-based approach.

Abstract

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.

• Authors: Giulio Poli, Tiziano Tuccinardi, Flavio Rizzolio, Isabella Caligiuri, Lorenzo Botta, Carlotta Granchi, Gabriella Ortore, Filippo Minutolo, Silvia Schenone, Adriano Martinelli
• Journal: Journal of chemical information and modeling (J Chem Inf Model) Vol. 53 Issue 10 Pg. 2538-47 (Oct 28 2013) ISSN: 1549-960X [Electronic] United States
• PMID: 24001328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Protein Kinase Inhibitors
• Small Molecule Libraries
• FYN protein, human
• Proto-Oncogene Proteins c-fyn

Topics

• Algorithms
• Area Under Curve
• Binding Sites
• Databases, Chemical
• Databases, Pharmaceutical
• Drug Discovery
• Enzyme Assays
• High-Throughput Screening Assays
• Humans
• Inhibitory Concentration 50
• Ligands
• Molecular Docking Simulation
• Protein Binding
• Protein Kinase Inhibitors (chemistry)
• Proto-Oncogene Proteins c-fyn (antagonists & inhibitors, chemistry)
• Small Molecule Libraries (chemistry)
• User-Computer Interface