Abstract: The MIFs was applied to a data set of 40 N-phenylhomophthalimide derivatives of APN inhibitors to generate the 3D-QSAR model at various 3D grid spacing. The cross-validated correlation coefficient q2LMO (0.6204) and r2pred (0.9810) were obtained at a 1.0 Å 3D grid spacing, indicating the statistical significance of this class of compounds. The calculated inhibitive activities showed a high degree of agreement with experimented values. Then, the 6 nsec MD simulation of protein-ligand complex and binding free energy analysis were carried out. The stable binding mode of the most active compound 21 was determined.