EGFR和4-苯胺喹唑啉类抑制剂之间相互作用模式的研究

Studies on Interactions between EGFR and 4-Anilinoquinazoline Inhibitors

采用分子动力学和MM PBSA相结合的方法预测了表皮生长因子受体和 4 苯胺喹唑啉类抑制剂的相互作用模式 .在分子动力学采样的基础上 ,采用MM PBSA的方法分别预测了四种可能结合模式下表皮生长因子受体和 4 苯胺喹唑啉类抑制剂间的结合自由能 .在MM PBSA计算中 ,受体和抑制剂之间的非键相互作用能采用分子力学(MM)的方法得到 ;溶剂效应中极性部分对自由能的贡献通过解Possion Boltzmanne (PB)方程的方法得到 ;溶液效应中非极性部分对自由能的贡献则通过分子表面积计算 (SA)的方法得到 .计算表明 ,在四种结合模式下 ,表皮生长因子受体和 4 苯胺喹唑啉类抑制剂之间的结合自由能有较大的差别 .在最佳的相互作用模式中 ,抑制剂的苯胺部分位于活性口袋的底部 ,能够与受体残基的非极性侧链产生很强的范德华和疏水相互作用 .抑制剂喹唑啉环上的N(1)原子能够和Met 76 9上的NH形成稳定的氢键 ,而抑制剂上的N(3)原子则和周围的一个水分子形成氢键 .同时 ,抑制剂双环上的取代基团也能和活性口袋外部的部分残基形成一定的范德华和疏水相互作用 .

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 Poisson-Boltzmann (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.