Inhibition of human epidermal growth factor receptor-2 protein by some alkaloid inhibitors

Abstract

BackgroundHuman Epidermal Growth Factor Receptor-2 (HER2), a transmembrane tyrosine kinase receptor, has been associated with several types of cancer, including breast, lung, ovarian, etc. Therefore, this receptor is targeted by a variety of therapeutic approaches for cancer treatments. The alkaloid and lead compounds are among the selective and potent HER2 inhibitors that have been reported so far. MethodsThe present work involves molecular docking, molecular dynamics (MD) simulations, and density functional theory (DFT) calculations on alkaloid and lead compounds as HER2 inhibitors. Significant findingsThe docking results expressed that the alkaloids mainly interacted with Cys805, Val734, and Ala751 residues of HER2 protein. The MD simulation outcomes represented that all the complexes have adequate dynamic stability and flexibility based on the root mean square deviation, root mean square fluctuation, and radius of gyration. Furthermore, it is found that the strongest HER2 − ligand interaction belongs to the nocamycin I (NOI, ΔGbind = -12.84 kcal mol−1) molecule. The DFT calculations showed that electron density and the second − order perturbation stabilization energy values for HER2 − NOI interactions are higher than the other complexes. The molecular docking, MD simulation, and DFT calculation results are all in agreement and complementary. It is expected that the results obtained here can present very helpful information for the design of efficacious inhibitors for the treatment of HER2 − related cancer disease.