Induced-fit docking and binding free energy calculation-on furostanol saponins from Tupistra chimensis as epidermal growth factor receptor inhibitors

摘要

Three furostanol saponins isolated from Tupistra chinensis were studied to investigate the reasons for their different inhibitory activities toward non-small-cell lung cancer (NSCLC) A549 cell using induced-fit docking (IFD) between them and epidermal growth factor receptor (EGFR). Their binding free energies were also calculated by molecular mechanics-generalized Born surface area (MM-GBSA) method. The calculation results were all in excellent agreement with experimental activities (IC_50 values of compound 1-3 against NSCLC A549 cell: 6.6,6.7, and 29.1 muM). With EGFR (PDB code: 1M17 and 2ITY), the docking IFD score, binding free energy, and binding free energy neglecting the effect of entropy contributions of compound 1 ((25R)-26-O-beta-D-glucopyranosyl-furost-lbeta,3beta,22alpha,26-tetrahydroxy-3-O-beta-D-glucopyranoside) were -553.9223, -59.6101, and -70.8088 kcal/mol in 1M17 (-536.2678, -62.2158, and -68.4053 kcal/mol in 2ITY), respectively. The binding sites of compound 1 are similar to erlotinib in 1M17 and gefitinib in 2ITY. There are two hydrogen bonds between compound 1 and the key amino acid residue Met769 in 1M17 or Met793 in 2ITY. The only structure difference between compound 3 and compound 1 is 5-hydroxyl polar group in compound 3, which hinders the hydrophobic interactions with EGFR and increases polar solvation free energy term that opposes binding. This indicates that compound 1 could be a potent EGFR inhibitor for NSCLC treatment.