Combined blockade of the renin-angiotensin-aldosterone system (RAAS) is an attractive therapeutic strategy for the treatment of cardiovascular diseases. Vasopeptidase inhibitors are a group of compounds capable of inhibiting more than one enzyme, which leads to potentiation of natriuretic peptide actions and suppression of the RAAS. In this study, molecular modeling has been used to elucidate key structural features that govern the binding and/or selectivity of a single compound toward the zinc catalytic sites of the N- and C-domains of the angiotensin-converting enzyme (ACE) and the neutral endopeptidase (NEP). Eleven dual inhibitors were categorized in three classes, according to their zinc binding groups. Analysis of their docked conformers revealed the molecular environment of the catalytic sites and the specific interactions between the inhibitors and amino acid residues that are important for selectivity and cooperativity. In addition, inhibitors were predicted to bind to the C-domain of the ACE with greater affinity than the N-domain, with an average difference in the free energy of binding approximately 2-3 kcal mol(-1). Residues that were identified to actively participate in the binding and stabilizing of the enzyme-inhibitor complexes were analyzed in a consensus way for both the ACE and the NEP. These atomic-level insights into enzyme-ligand binding can be used to drive new structure-based drug design processes in the quest for more selective and effective vasopeptidase inhibitors.