Molecular Simulation of HER2/neu Degradation by Inhibiting HSP90

Several flavonoids were investigated for the degradation of the HER2/neu (ErbB‐2), while the mechanism is still unknown. A hypothesis was generated here that the inhibition of HER2/neu expression was blocked by heat shock protein 90α (HSP90α) through 1‐benzyl‐3‐(5‐hydroxymethyl‐2‐furyl)indazole (YC‐1) derivatives and flavonoids. In order to ensure the accuracy of the simulated protein structure, the RMSD value between the ligand in crystal structure from PDB and the ligand docking into HSP90α was 1.13 Å. By molecular simulation, the flavonoids and YC‐1 derivatives were employed to dock into HSP90α. The results showed a good correlation between the evaluation scores of the flavonoids/HSP90α complexes and the IC₅₀ of flavonoids‐induced degradation of HER2/neu. The YC‐1 derivatives showed higher score values and lower interaction energies on average. Especially, the CLC107 got the highest rank in Potential of Mean Force (PMF) and Dock Score. Luteolin showed the highest dock score and quercetin had the lowest interaction energy of all flavonoid derivatives. This study investigated that the YC‐1 derivatives and the flavonoids may be potent inhibitors for HSP90α in antitumor strategies.