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
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.