### EGFR和4-苯胺喹唑啉类抑制剂之间相互作用模式的研究

1. 北京大学化学与分子工程学院北京大学养生堂天然药物研究室.北京(100871)
• 发布日期:2002-06-15

### Studies on Interactions between EGFR and 4-Anilinoquinazoline Inhibitors

Hou Tingjun;Zhu Lili;Chen Lirong;Xu Xiaojie

1. College of Chemistry and Molecular Engineering, Beida Yang Sheng Tang Joint Laboratory for Natural Product.Beijing(100871)
• Published:2002-06-15

The possible binding mode between EGFR and a 4-anilinoqunazoline inhibitor was predicted by using molecular dynamics and MM/PBSA. Based on the trajectories from MD simulations, the free energies of binding for four types of possible binding modes were calculated using MM/PBSA technique. In MM/PBSA calculations, the sum of nonbonded energies between inhibitor and receptor were computed using molecular mechanics (MM). The polar solvation energies contributed to binding were computed using a finite-difference Possion-Boltzmanne (PB) model, while the nonpolar solvation energies contributed to binding were obtained from the solvent-accessible surface area (SA). The calculated results show that among these four types of binding models there exist large differences in the binding free energies between EGFR and 4- anilinoqunazoline. In the best binding mode, the 4-phenylamino group is located deep in the binding cleft, which can produce favorable van der Waals and hydrophobic interactions with the nonpolar side chains of the residues. The N(1) atom of the quinazoline can form a stable H- bond with Met-769, while the N(3) atom can form a H-bond with a water molecule. Moreover, the substituents on the bicyclic chromophore can also produce strong van der Waals and hydrophobic interactions with the residues located at the exterior part of the binding pocket. The relationships between the structures and activities of available inhibitors can be well explained in terms of the best binding mode.