Virtual screening to design drug molecules for human proto oncogene Fyn kinase

AbstractHuman Fyn tyrosine kinase, a Src-family enzyme plays a pivotal role in the integrin mediated cell signaling pathway and is known to interact with several molecular signals including FAK and paxillin that accounts for morphogenic transformation leading to cancer. The present study was aimed to design a persuasive inhibitor for Fyn kinase. The crystal structure was optimized and energy minimized applying OPLS2001 force field in Maestro v9.0. The inhibitor binding site residues such as LEU-17, GLY-18, ASN-19, VAL-25, ALA-37, LYS-39, GLU-54, THR-82, GLU-83, TYR-84, MET-85, GLY-88, ALA-134, ASN-135, LEU-137, and ASP-148 were located from the Fyn kinase co-crystal structure with staurosporine. Three published inhibitors (staurosporine, Rosmarinic acid and dasatinib) of Fyn kinase were searched through high throughput virtual screening in Ligand.Info Metadatabase and generated 1163 structural analogues. Glide 5.5 docking was performed to predict the binding orientation of prepared ligand molecule into a grid of 20 x 20 x 20 Å created around the centroid of optimized Fyn kinase. Isomers and tautomers were generated for 1163 chemical entities through LigPrep. Ligands having reactive functional groups and poor ADME properties were rejected from the prepared dataset and docked into the predicted active site of human Fyn kinase through a systematic application of virtual screening using Glide v5.5. Five lead molecules with good XP GScores were obtained with their binding orientations, further XP Gscores were interrelated with the existing three published inhibitors. Lead1 (nor dihydroguaiaretic acid) was observed to have the lowest XP Gscore (-11.39 Kcal/mol) compared to three published inhibitors and blocked the Fyn kinase active site by forming hydrogen bonds and good Van der Waals contacts. Thus, nor dihydroguaiaretic acid would be useful as drug molecule if synthesized and tested in animal models.