In Silico Analysis To Explore Novel Inhibitors For Human Proto-oncogene Tyrosine Protein Kinase Src

The first oncogene and the first non receptor tyrosine kinase, Src, plays a key role in cell morphology, motility, proliferation and survival. Over expression of Src kinase activity disrupts the RAS pathway in signaling pathway, where it loses its ability to hydrolyse GTP and thus, leads to cancer. A wide range of evidences indicated that Src-signaling was important in the oncogenesis of prostate cancer and other tumours. Src-signaling is involved in androgen-induced proliferation of prostate cancer in cancer tissue of patients having castration-refractory prostate cancer. Once prostate cancer becomes castration-resistant, bone metastases become significant problem for which treatment options are limited. As Src is involved in multiple signaling pathways, central to prostate cancer development, progression, and metastasis, in addition to normal and pathologic osteoclast activities, Src inhibition becomes a valid therapeutic strategy for investigation. Existing Src kinase inhibitors are less efficient towards prostate cancer and bone metastasis. Hence an in silico work was carried out to identify novel potent inhibitors. Three published inhibitors of human Src kinase those are currently under clinical trial such as AZDO530, bosutinib and dasatinib were subjected to high-throughput screening from more than million entries of Ligand.Info Meta-Database, based on the assumption that small molecules with similar structure have similar pharmacological properties. The ligand dataset of 1152 generated through this approach were prepared using LigPrep to generate possible conformations of each ligand molecule, and at the same time duplicate conformers, conformations with reactive functional group and ADME violaters were rejected. The human Src kinase co-crystal structure with AZDO530 was analyzed to find the inhibitor binding site. The crystal structure was optimized and energy was minimized applying OPLS force field in Maestro v9.0. 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 human Src kinase. Ten lead molecules with good binding affinity with human Src were identified. In silico pharmacokinetics study for these ten lead molecules had shown no ADME violation. Analysis of Lead ‘1’ - human Src docking complex had revealed a XP Gscore of -11.56 kcal/mol with highly stabilized hydrogen bond network with Ala390, Asn391, Lys295, W543 and W640 and good Van der Waals interactions. The docking complex coincides well with the native co-crystallized human Sac and inhibitor AZDO530 complex. Thus, Fisetin, identified as Lead ‘1’ in the present study would be highly useful for developing potential drug molecules for treatment of advanced prostate cancer