Neprilysin-2 (NEP2) in the central nervous system controls Alzheimer's protein (amyloid-β) deposition, and prevents its occurrence. However, in the peripheral system, its closest homolog, neutral endopeptidase (NEP), regulates hypertension and heart related diseases. Inhibitors of NEP with a lesser degree of specificity can treat hypertension with an increased risk of cerebral deposition of amyloid-β. In order to rationalize the point of selectivity, the dynamic behavior of human NEP and NEP2 proteins was monitored by conducting molecular dynamics (MD) simulations. A computationally reliable model of NEP2 was achieved with 79.9%, 19.1% and 0.2% residues in the allowed, additionally allowed and disallowed regions respectively, using as a reference protein. Additionally, molecular docking studies were carried out for a set of five already known inhibitors of NEP and modeled NEP2 to obtain the comparative behaviors of the complexes. MD results highlighted their different responses along with important residues having a part in ligand-protein binding. For substrate and inhibitor binding, Arg664/661 and Zn697/694 were identified as the most conserved residues. High degree flexible transitions during the MD simulations were also observed in loop areas along with active site residues. Energy calculations, hydrogen bonds and their occupancy rates helped to conclude each ligand's potency towards a particular target. In most complexes of hNEP2, the ligands showed weak interactions which might be due to its larger pocket size or huge conformational variations in active site residues upon complexation. In the case of inhibitors of a small size like thiorphan, Arg49 and Arg664 are found to be acting to support the ligand binding in NEP while only Arg661 is acting in NEP2.