Molecular Insight and Binding Pattern Analysis of Shikonin as a Potential VEGFR-2 Inhibitor

Background: Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) is one of the proangiogenic factors that promotes endothelial cell proliferation, migration, differentiation, tube formation and thus helps in the angiogenesis and progression of cancers. Considering the VEGFR-2 as a prominent target for angiogenesis inhibition, the present study was focused to a potent phytochemical shikonin as potential lead molecule. Method: Different computational analysis like docking, QM/MM (Quantum Mechanics/Molecular Mechanics), stochastic dynamics simulation, mutagenesis and ADME/T with SoM predictions were employed to understand the binding behavior of shikonin with VEGFR-2 and also its toxicity and metabolic profile. Results: From the docking, QM/MM and in silico mutagenesis analysis, it was concluded that the residues like ASP1046, GLU885, LEU889, LEU1019, and LYS868 are major for ligand binding and inhibition. Moreover, shikonin processed strong binding with VEGFR-2 by forming non bonded interactions, and revealed as a non ATP non-competitive inhibitor; which was further confirmed by stochastic dynamics simulations. And also, it is less toxic and has moderate oral absorption rate. Conclusion: This study will be useful for the designing of new inhibitor against VEGFR-2, by selecting shikonin as a lead molecule, and also for the development of shikonin's derivatives for single or combination therapy against angiogenesis and cancer.