Homology modeling of human Fyn kinase structure: discovery of rosmarinic acid as a new Fyn kinase inhibitor and in silico study of its possible binding modes

Tyrosine phosphorylation represents a unique signaling process that controls metabolic pathways, cell activation, growth and differentiation, membrane transport, Apoptosis, neural, and other functions. We present here the three-dimensional structure of FYN tyrosine kinase, a Src-family enzyme involved in T-cell receptor signal transduction. The structure of FYN was modeled for homology using the Sybyl-Composer suite of programs for modeling. Procheck and Prosa II programs showed the high quality of the obtained three-dimensional model. Rosmarinic acid, a secondary metabolite of herbal Plants, was discovered as a new FYN kinase inhibitor using immunochemical and in silico methods. Two possible binding modes of rosmarinic acid were evaluated here, i.e., near to or in the ATP-binding site of kinase domain of FYN. Enzyme kinetic experiments revealed that FYN is inhibited by a linear-mixed noncompetitive mechanism of inhibition by rosmarinic acid. This indicates that rosmarinic acid binds to the second "non-ATP" binding site of the FYN tyrosine kinase.