The further interaction mechanism towards renin inhibitors was revealed by comparison of renin with different active inhibitors in aqueous solution. Molecular docking and molecular dynamics (MD) simulations were combined for the research. The results reflected that electrostatic and hydrophobic effects were the major interactions for renin inhibitors forming complexes with renin, and some residues were the key to the formation of complex, especially Asp38/Asp226. The factor of different activities performed in renin inhibitors was illustrated as well. For the higher active renin inhibitor, it possessed stronger affinity with renin, and its detected conformation was more extended to fit for the key binding site. This promoted the capacity to form special interactions with the key residues. While conformation of the lower active renin inhibitor performed folded in the active site of renin, the interactions to the important pocket S3sp was restricted, resulting in undesirable bioactivity.