Screening of multi-targeted natural compounds for receptor tyrosine kinases inhibitors and biological evaluation on cancer cell lines, in silico and in vitro.

Receptors for growth factors encompass within the superfamily of receptor tyrosine kinases and are known to regulate numerous biological processes including cellular growth, proliferation, metabolism, survival, cell differentiation and apoptosis. These receptors have recently caught the attention of the researchers as an attractive target to combat cancer owing to the evidence suggesting their over-expression in cancer cells. Therefore, we studied receptor-based molecular docking of IR (PDB; 3ETA), IGF1R (PDB; 1K3A), EGFR (PDB; 1M17), VEGFIR (PDB; 3HNG), and VEGFIIR (PDB; 2OH4) against natural compounds. Further, in vitro investigation of the biological effect of lead molecules in an array of cancer cell lines was done. All selected natural compounds were docked with the X-ray crystal structure of selected protein by employing GLIDE (Grid-based Ligand Docking with Energetics) Maestro 9.6. InterBioScreen natural compounds docked with each selected protein molecules by using GLIDE high throughput virtual screening. On the basis of Gscore, we select 20 compounds along with 68 anticancer compounds for GLIDE extra precision molecular docking. It was discovered in this study that compound epigallocatechin gallate (EGCG) yielded magnificent Gscore with IGF1R (PDB; 1K3A) and VEGFIIR (PDB; 2OH4), and protein-ligand interactions are chart out. Effect of EGCG on biological activity such as mRNA expression of selected protein, cell proliferation, oxidative stress, and cell migration was reported after the 48 h treatments in cancer cell lines. The RT-PCR densitometric bands analysis showed that compound EGCG reduced the mRNA expression of IGF1R, VEGFIIR, and mTOR at 80 μM concentration. Moreover, EGCG significantly reduced cell proliferation and ROS generation after 48 h treatments. Our result also indicated a reduction in the potential for cell migration that might show in vivo anti-metastasis activity of EGCG.