Molecular dynamics simulation, free energy landscape and binding free energy computations in exploration the anti-invasive activity of amygdalin against metastasis

Background and objective: Historically, amygdalin has been used as alternative medicine or in vitro and in vivo studies, but no single study exists which discusses the structural mechanism of amygdalin at a molecular level. This paper inquiries into the inhibitory actions of amygdalin on the selected targets: AKT1, FAK, and ILK, which are regulators for various mediated signaling pathways, and are associated with cell adhesion, migration, and differentiation. In order to get details at the molecular level of amygdalin's inhibitory activities against chosen proteins, molecular modeling and simulation techniques including double docking, molecular dynamics simulation, free energy landscape analysis, and binding free energy calculation were exerted.

Methods: To get molecular level details of amygdalin inhibitory effects against the relevant proteins; here the utilized tools are the following: the double docking, molecular dynamics simulation, free energy landscape analysis, g_mmpbsa, and interaction entropy were used to evaluate the inhibitory activity against targeted proteins.

Results: The computational calculations revealed that amygdalin inhibits the selected targets via block the ATP-binding pocket of AKT1, FAK, and ILK by forming stable hydrogen bonds. Moreover, free energy landscape, FEL exposed that amygdalin stabilized the global conformations of both FAK and ILK proteins to the minimum global energy besides it reduced the essential dynamics of FAK and ILK proteins. MMPBSA computations provided further evidence for amygdalin's stability inside the ATP-binding pocket of AKT1, FAK, and ILK with a binding free energy of 45.067, -13.033, 13.109 kJ/mol, respectively. The binding free energies are lastly consistent with the hydrogen bonding and pairs within 0.35 nm results. The decomposition of binding energy shows the pivotal amino acid residues responsible for the stability of amygdalin's interactions inside the ATP-binding sites by forming hydrogen bonds.

Conclusions: Before this work, it was enigmatic to make predictions about how amygdalin inhibits metastasis of cancer. But the computational results contribute in several ways to our understanding of amygdalin activity and provide a basic insight into the activity of amygdalin as a multi-target drug in the metastasis and invasion of cancer.