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.

Key words: ANILINE P, QUINAZOLINE, INHIBITOR, STRUCTURE AND PROPERTY CORRELATION, molecular dynamics