Background: Fyn kinase involved in a variety of different signalling pathways. Their abnormal activity has been shown to be related to severe pathologies, such as Alzheimer’s and Atherosclerosis diseases making Fyn an attractive target for the discovery of potential novel therapeutics for these diseases. Given the lack of a specific Fyn inhibitors even though the great number of compounds active on other members of Src family or on different tyrosine kinases; we carried out a study to identify new Fyn kinase inhibitors by suggesting inhibitors scaffold more active and selective against Fyn kinase.
Results: The first part of the study was devoted to the generation of two-dimensional (2D) quantitative structure-activity relationship (QSAR) models to compounds with known IC50 values. These molecules belong to type I and type II inhibitors. 2D-QSAR models were validated and were proved to be reliable models useful to predict activity enhancements for new compounds. Pharmacophore models were also created and the interaction between Fyn kinase and the most active inhibitors were studied by the docking-based virtual screening. Molecular docking related to the prediction of three-dimensional (3D) structure of Fyn kinase on DFG-out conformation and obtained conformation was evaluated by the principal methods of 3D-structure validation.
Conclusion: These studies provide a basis for efficiently validate, design and screen a large number of most potent and selective inhibitors against Fyn kinase.