Small Molecules From Vernonia Amygdalina (Del.) As Promising Agents For Kras-Driven Tumors
Keywords:In Silico, Vernonia Amygdalina, Kras, Schrodinger, Molecular Docking
In spite of advances in medicine, cancer remains the second leading cause of death, accounting for 1 in every 6 deaths globally. Numerous oncogenes have been identified to be constitutively active in cancer due to genetic alterations. A notable and hard-to-hit one is the Kras (Kirsten rat sarcoma). Howbeit, resistance and toxicity from synthetic drugs have reduced the survival rate, causing most cancer patients to seek natural remedies with fewer side-effects as alternatives. This study was conducted to investigate the Kras inhibitory effect of small molecules from Vernonia amygdalina, utilizing in silico approach. A G12C mutated KRas protein was retrieved from Protein Data Bank while the structures of the compounds were collected from PubChem database. Both structures were prepared using the protein preparation and ligprep wizard of the Schrodinger Suite. The castP (Computed Atlas of Surface Topography of proteins) server was employed to identify pockets in KRas before the docking studies with the Glide, Schrodinger Suite. The docking protocol was validated with a RMSD of 0.1724 and binding orientation, similar to the co-crystal ligand. The docking poses and orientations were taken for each compound and the forces of interactions were all considered. From the results, compounds from V. Amygdalina, showed good binding interactions with active amino acids reported in mutated Kras inhibition. These binding stabilized the protein in the off state, reducing undue proliferation and downstream signaling. It is therefore promising, that these compounds could restore the lost intrinsic GTPase activity of KRas driven tumors, if taken into further studies.